Methods for treating neurological disorders or damage

ABSTRACT

A clonogenic neurosphere assay is described that carries out high throughput screens (HTS) to identify potent and/or selective modulators of proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/or self-renewing and multipotent neural stem cells (NSCs). Compositions comprising the identified modulators and methods of using the modulators and compositions, in particular to treat neurological disorders (e.g. brain or CNS cancer) or damage are also disclosed.

BACKGROUND OF INVENTION

The invention relates to compositions and methods to treat neurological disorders or damage, in particular brain or CNS cancer.

The identification of self-renewing and multipotent neural stem cells (NSC) in the mammalian brain holds promise for the treatment of many neurological diseases and has yielded new insight into brain cancer (5-7). However, the NSC “ground state”—defined by the complete repertoire of pathways that govern NSC proliferation, self-renewal and differentiation—remains largely uncharacterized. The in vitro culture of embryonic or postnatal brain cells isolated from anatomic precursor compartments in serum-free conditions containing FGF and EGF results in the expansion of a rare subpopulation of precursor cells and the formation of floating clonogenic clusters termed neurospheres (8-10) (FIG. 1 a,b). Analysis of these neurosphere cultures has made it possible to elucidate the individual roles of developmental signaling pathways including the PTEN, Bmi 1, Notch, Wnt and Sonic Hedgehog (Shh) pathways in neural precursor proliferation, in concert with the known functions of these pathways in vivo (11-15). Although the candidate gene approach has been successful at uncovering vital pathways in NSC biology, to date only a small set of highly-studied networks has been sampled.

SUMMARY OF INVENTION

Applicants have developed a clonogenic neurosphere assay to carry out high throughput screens (HTS) to identify potent and/or selective modulators of proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs. The modulators disclosed herein and/or identified by a method described herein are also referred to herein as “NSC Modulating Agents”.

In one aspect, a method is provided for identifying putative NSC Modulating Agents comprising incubating a neurosphere culture in the presence of a test agent and determining the effect of the test agent on proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs in the culture, wherein a difference in proliferation and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs compared with a control neurosphere culture indicates that the test agent is a putative NSC Modulating Agent.

A method further comprises assessing the selectivity and/or potency of a putative NSC Modulating Agent by determining the effect of a putative NSC Modulating Agent on a normal astrocyte cell line. In an aspect, selectivity and/or potency are assessed by constructing dose-response curves and EC₅₀s for the normal astrocyte cell line and calculating a neurosphere selectivity ratio. A neurosphere selectivity ratio can be defined as EC₅₀ astrocytes/EC₅₀ precursor cells. A neurosphere selectivity ratio greater than that observed in controls indicates that the putative NSC Modulating Agent is potent and/or selective. Therefore a method may further comprise assessing the selectivity and/or potency of a putative modulator by comparing a neurosphere selectivity ratio of the modulator in a normal astrocyte cell line to that of a control. In certain embodiments, the controls comprise cycloheximide, etoposide and carboplatin. In other embodiments, the neurosphere selectivity ratio is greater than 3, 4, 5, 6, 7, 8, 9 or 10.

Using the methods described herein, modulators have been identified that modulate proliferation, differentiation and/or renewal of normal and diseased (e.g. cancerous) neural precursor cells, neural progenitor cells and/or NSCs.

In another aspect, a composition comprising one or more NSC Modulating Agents, and a pharmaceutically acceptable carrier, excipient or diluent is provided.

In a further aspect, a composition is also provided and comprises one or more NSC Modulating Agent in a therapeutically effective amount for inhibiting proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs, in particular diseased (e.g., cancerous) neural precursor cells, neural progenitor cells and/or NSCs.

In one embodiment, a composition comprising one or more NSC Modulating Agent in a therapeutically effective amount for treatment of a brain or CNS cancer, more particularly a primary CNS tumor is further provided.

In another embodiment, a composition comprising one or more NSC Modulating Agent in a therapeutically effective amount for treatment of a brain tumor having a genetic profile resembling that of normal and embryonic neural precursor cells is also provided.

In another embodiment, a composition comprises one or more NSC Modulating Agent in a therapeutically effective amount for treatment of a brain tumor enriched for cancer stem cells.

In other embodiments of compositions for treating a condition requiring inhibition of proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs, the NSC Modulating Agents in the composition are one or more agents that modulate neurotransmission in the dopamine, serotonin, opioid, glutamate, and/or vanilloid pathways. More particularly, the NSC Modulating Agents in the composition are one or more of a dopamine receptor antagonist, a dopamine receptor agonist, an acetylcholine receptor antagonist, an NMDA receptor antagonist, an opioid receptor agonist, a retinoic acid receptor agonist, a JAK3 antagonist, a p38 MAPK antagonist, a serotonin receptor agonist, or a vanilloid receptor agonist. Most particularly the NSC Modulating Agents are one or more of (±)butaclamol, R(−) propylnorapomorphine, apomorphine, cis-(Z) flupenthixol, hexahydro-sila-difenidol, ifenprodil tartrate, carbetapentane citrate, fenretinide, WHI-P131, SB 202190, p-aminophenethyl-m-trifluoromethylphenyl piperazine (PAPP), and dihydrocapsaicin. In certain aspects, the NSC Modulating Agent in the composition is one or both of apomorphine and ifenprodil.

In another aspect, a composition comprises one or more NSC Modulating Agent in a therapeutically effective amount for inducing proliferation of normal neural precursor cells and/or neural progenitor cells.

In still another aspect, a composition comprising one or more NSC Modulating Agent in a therapeutically effective amount for inducing differentiation and/or renewal of normal neural precursor cells, neural progenitor cells and/or NSCs is further provided.

In yet a further aspect, a composition comprises an NSC Modulating Agent in a dosage effective for inducing proliferation of neural stem cells into an increased amount of neural progenitor cells, or for inducing proliferation of neural stem cells or neural progenitor cells into an increased amount of neural cells, e.g., glia, neurons, astrocytes and/or oligodendrocytes.

In another aspect, a composition for treatment of a neural disorder, in particular a neurological disease, neurodegenerative disease, or central nervous system (CNS) trauma is provided and comprises an NSC Modulating Agent in a dosage effective for inducing proliferation of neural stem cells into an increased amount of neural progenitor cells.

In yet another aspect, a composition is provided for treatment of a neural disorder, in particular a neurological disease, neurodegenerative disease, or central nervous system (CNS) trauma comprising an NSC Modulating Agent in a dosage effective for inducing proliferation and/or differentiation of neural stem cells or neural progenitor cells into an increased amount of neural precursor cells or neural cells, e.g., glia, neurons, astrocytes and/or oligodendrocytes.

Proliferation, differential and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs neural precursor cells may be induced ex vivo or in vivo. The composition can be in a pharmaceutically acceptable carrier, excipient, or vehicle.

Additionally provided is a method of preparing a stable pharmaceutical composition comprising one or more NSC Modulating Agent. A method can comprise mixing one or more NSC Modulating Agent and a pharmaceutically acceptable carrier, excipient, or vehicle, in particular, a pharmaceutically acceptable carrier, excipient, or vehicle which may be effective to physically stabilize the compound(s). After compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a composition described herein, such labeling would include amount, frequency, and method of administration.

NSC Modulating Agents may be used in the treatment of conditions that require modulation of proliferation, differentiation and/or renewal of normal or diseased neural precursor cells, neural progenitor cells and/or NSCs.

Therefore, in an aspect, a method is provided for treating or preventing a condition requiring modulation (e.g., inhibition) of proliferation, differentiation and/or renewal of diseased neural precursor cells, neural progenitor cells and/or NSCs comprising administering to a subject in need thereof a therapeutically effective amount of an NSC Modulating Agent or a composition of the invention. In embodiments of this aspect, the NSC Modulating Agent is one or more of a dopamine receptor antagonist, a dopamine receptor agonist, an acetylcholine receptor antagonist, an NMDA receptor antagonist, an opioid receptor agonist, a retinoic acid receptor agonist, a JAK3 antagonist, a p38 MAPK antagonist, a serotonin receptor agonist, or a vanilloid receptor agonist. More particularly, the NSC Modulating Agents are one or more of (±)butaclamol, R(−) propylnorapomorphine, apomorphine, cis-(Z) flupenthixol, hexahydro-sila-difenidol, ifenprodil tartrate, carbetapentane citrate, fenretinide, WHI-P131, SB 202190, p-aminophenethyl-m-trifluoromethylphenyl piperazine (PAPP), and dihydrocapsaicin.

In another aspect, a method for treating or preventing a condition requiring modulation of proliferation, differentiation and/or renewal of normal neural precursor cells, neural progenitor cells and/or NSCs is provided and comprises administering to a subject in need thereof a therapeutically effective amount of an NSC Modulating Agent or a composition described herein.

Also contemplated is the use of an NSC Modulating Agent or a composition described for the preparation of medicaments for treating or preventing a condition requiring modulation of proliferation, differentiation and/or renewal of normal or diseased neural precursor cells, neural progenitor cells and/or NSCs. Additionally provided are uses of a pharmaceutical composition described herein in the preparation of medicaments for the prevention and/or treatment of conditions and/or diseases disclosed herein.

The invention has particular application in preventing and/or treating brain or CNS cancer. Thus, a method of treatment is provided and comprises administering a therapeutically effective amount of one or more NSC Modulating Agent or a composition described herein which upon administration to a subject with symptoms of a brain or CNS cancer produces beneficial effects, preferably sustained beneficial effects (e.g., inhibition of proliferation, differentiation and/or renewal of normal or diseased neural precursor cells, neural progenitor cells and/or NSCs), in particular cancerous neural precursor cells.

In an embodiment, a method is provided for preventing and/or treating a primary CNS tumor comprising administering a therapeutically effective amount of one or more NSC Modulating Agent or a composition discussed herein.

In a further embodiment, a method for ameliorating progression of a condition and/or disease or obtaining a less severe stage of a condition and/or disease in a person suffering from a brain or CNS cancer, in particular a primary CNS tumor, is provided and comprises administering a therapeutically effective amount of one or more NSC Modulating Agent or a composition discussed herein.

A method of delaying the progression of a brain or CNS cancer, in particular a primary CNS tumor, is further provided and comprises administering a therapeutically effective amount of one or more NSC Modulating Agent or a composition provided herein.

A kit is also provided and comprises one or more one or more NSC Modulating Agent or a composition described herein. In an aspect, a kit is provided for preventing and/or treating brain or CNS cancer, containing a composition comprising one or more NSC Modulating Agent or a composition described herein, a container, and instructions for use. The composition of the kit can further comprise a pharmaceutically acceptable carrier, excipient, or vehicle.

These and other aspects, features, and advantages of the present invention should be apparent to those skilled in the art from the following drawings and detailed description.

DESCRIPTION OF DRAWINGS

FIG. 1 shows a Schematic of HTS of neural precursor cells (a) Neurospheres are derived from self-renewing multi-potent NSCs and contain a heterogeneous mixture of stem, progenitor, and a very small number of differentiated cells. (b) Light microscope image of neurospheres grown for seven days at clonal density. Scale bar, 100 μM (c) Schematic of the small molecule screen. Primary neurospheres were dissociated and screened against small molecules in 96-well plates. Compounds that affect neural precursor proliferation (including NSC self renewal) were identified with an MTT proliferation assay and verified hits interrogated in other assays.

FIG. 2 shows the HTS of neurosphere cultures. (a) Scatter plot of all 1,267 compounds of the LOPAC™ library screened against neural precursor cells. One hundred sixty compounds (∘) were identified as inhibitors of neurosphere proliferation (P<0.01), 19 compounds (□) were identified as activators (P<0.01) and the rest of the agents (▴) screened did not have any significant effects on proliferation (P>0.01). (b) Examples of phenotypic variation observed in response to particular agents. Scale bars, 250 μM.

FIG. 3 shows the identification of potent neural precursor cell-specific compounds. Dose-response curves and chemical structures of controls: (a) cycloheximide, (b) etoposide, and (c) carboplatin, and selected newly identified compounds: (d) dihydrocapsaicin, (e) apomorphine, and (f) PAPP. Each plot displays the fitted sigmoidal logistic curve to MTT proliferation assay readings of both astrocytes (- -•- -) and neurosphere cultures (-▴-). All points represent the mean of triplicates from three independent experiments; standard error of the mean (s.e.m.) is shown. (g) Replating colony forming efficiency of pretreated neurosphere cultures. Values represent the number of secondary neurospheres arising from an inoculum of 2000 or 1000 cells following a seven day pretreatment with the indicated inhibitor at the estimated EC₇₅ value. As the EC₇₅ of apomorphine did not allow the recovery of sufficient cells, an EC₅₀ pretreatment was used for this agent. All values represent the mean of 6 replicates from two independent experiments; s.e.m. is shown. Asterisks indicate that the replating efficiency of the treated precursor population was significantly reduced (P<0.05) compared to corresponding control at both cell densities.

FIG. 4 shows the promiscuous neurotransmitter drug sensitivity in medulloblastoma precursor cells. (a) Cells isolated from ptc1^(+/−) tumors contain self-renewing neurosphere-forming cells in vitro. (b) Ptc1^(+/−) tumors contain cells that stain positive (M1) for the early precursor marker Prominin1 (CD133 homolog) at comparable levels to primary human medulloblastomas (11.6%). Unstained (black) and stained (red) specimens are shown. (c) EC₅₀ values for inhibition of tumor sphere MTT proliferation by various neurotransmission agents. Values represent the average and standard deviation of triplicate cultures. (d, e) Functional ground state of NSCs: (d) Current models of the NSC hierarchy focus on developmental signaling pathways such as Wnt, Notch, and Sonic Hedgehog. (e) Compounds identified in the HTS approach reveal that the NSC ground state and cell fate decision-making depends on a complex circuitry that includes many neurotransmission signaling pathways.

FIG. 5 shows the validation of a HTS assay for neurosphere cultures. (a) Scatter plot of positive (3 μM cycloheximide) and negative controls (vehicle: 0.03% DMSO) demonstrate the dynamic range of the HTS neurosphere assay. Z′-factor analysis confirmed the suitability of the assay for screening. (b) Pearson R correlation of pilot experiments performed in replicate demonstrated reproducibility and accuracy of values over the dynamic range of the screen.

FIG. 6 shows the confirmation of HTS hits. Normalized MTT values of a representative sample of hits taken from different pharmacological classes in the LOPAC™ library collection. Compounds are annotated by Sigma-Aldrich catalog number. All values represent the mean of triplicate values of three independent experiments and error bars represent s.e.m. Of the 43 compounds retested, 40 (93%) (blue) were confirmed as significant (P<0.05) when compared to control wells (green) using Student's t-test.

FIG. 7 shows the assessment of plate edge effects. Optical density scatter and mesh plot of MTT values as a function of well row and column are shown. Due to the long incubation time of plates at 37° C., a row and column-dependant edge effect emerged due to differential evaporation over the course of the screen. Systematic noise was removed as described in FIG. 8.

FIG. 8 shows the correction for plate edge effects in the screen. (a) Density function of the raw data obtained from the HTS of neurospheres prior to the correction for edge-effects. (b) Density function of the normalized (black line) and the fitted theoretical distribution (red line) used to calculate significance. (c) Box plot representation of the raw data of each plate in the screen. (d) Re-plot of data after the removal of the evaporation induced systematic error helped to reduce the number of both false positives and negatives. Box length for each plot represents the interquartile range (IQR) (Q3-Q1). The solid black line represents the median value for each plate and cutoffs represent values 1.5*(IQR) from Q3 and Q1.

FIG. 9 shows the temporal effects of depression on the brain tumor standardized incidence ratio (SIR). Frequency of brain tumors (expressed as standard incidence ratio; SIR) in patients diagnosed with depression. Unlike other cancers, the SIR of brain tumors exhibits an initial significant rise following diagnosis of depression, which is subsequently followed by a progressive decrease in SIR with time. Data for this figure were extracted from Dalton, S. O., et al. Am. J. Epidemiol 155, 1088-1095 (2002).

FIG. 10 shows the identification of potent NPC-specific compounds. (a-f) Dose-response curves and chemical structures of controls: cycloheximide (a), etoposide (b) and carboplatin (c), and of selected newly identified compounds: dihydrocapsaicin (d), apomorphine (e) and PAPP (f). Each plot shows the fitted sigmoidal logistic curve to MTT proliferation assay readings of both astrocytes (- -•- -) and neurosphere cultures (-▴-). Values represent the mean and s.e.m. of three independent experiments. (g) Replating colony forming efficiency of pretreated neurosphere cultures. Values represent the number of progeny neurospheres arising from 2,000 or 1,000 cells plated in fresh medium after a 7-d pretreatment of NPCs with the indicated inhibitor at the estimated EC₇₅ value. As the EC₇₅ of apomorphine did not allow the recovery of sufficient cells, an EC₅₀ pretreatment was used for this agent. Sphere counts for vehicle treated cells represent the mean and s.d. of six separate replicates conducted during two independent experiments. All other values represent the mean of two independent experiments. Asterisks indicate a reproduced statistically significant (P<0.05) reduction in replating efficiency when compared to vehicle control. The larger P value (of the two experiments) is reported. These differences (at both 2,000 and 1,000 cells per well) were confirmed (two-tailed paired t-test) for cultures treated with PAPP (P_(2,000)=0.02; P_(1,000)=0.008) and apomorphine (P_(2,000)=0.01; P_(1,000)=0.02) in three independent trials.

FIG. 11 shows temporal effects of neuromodulators on NPC viability and apoptotic response. (a) Proliferation dynamics of PAPP-, ifenprodiland etoposide-treated NPCs. (b) Normalized caspase-3 and caspase-7 activity in NPCs after 12 h and 48 h of drug treatment. Asterisk indicates a significant change (two-tailed t-test) from the corresponding vehicle-treated data point. (c) Corresponding MTT values taken at 12 h and 2 d for the caspase-3 and caspase-7 experiments shown in b. All values represent the mean and s.d. of one representative experiment (from three independent trials) of NPCs treated with PAPP (1 μM), ifenprodil (3 μM), etoposide (3 μM) or vehicle. (d) Flow cytometric analysis of the neural precursor marker nestin in NPCs after 2 d of treatment with ifenprodil (5 μM) or vehicle. Representative histograms of vehicle treated (20% nestin negative) and ifenprodil treated (63% nestin negative) cells compared with the isotype control (100% nestin negative) are shown from two independent experiments.

FIG. 12 shows neuromodulator drug sensitivity in normal and cancerous NPCs. (a) Ptch1+/− tumors contain cells with self-renewing neurosphere-forming potential in vitro. Scale bar, 125 mm. (b) Ptch1+/− tumor cells stain positive (M1) for the early precursor marker prominin-1 (CD133 homolog) at levels comparable to those of primary human medulloblastomas (11.6%)(4). Unstained (black) and stained (red) specimens are shown. (c) EC50 values (mean and s.d.) for inhibition of Ptch1^(+/−) Trp53^(−/−) tumor sphere MTT proliferation by various neuromodulators. Compound identity indicated in Table 2. (d) RT-PCR gene expression profiles of a selection of neurotransmitter receptors in different precursor populations. mRNA from serum-differentiated neurospheres and mouse erythroid leukemia (MEL) cells were used as positive and negative controls, respectively. Vertical black line indicates noncontiguous lanes from the same experiment. (e) Inhibition of colony formation by bromocriptine in cultures with and without (±)-sulpiride supplementation. Normalized mean and s.e.m. values of three independent triplicate cultures are shown. Sulpiride challenge significantly shifted the EC₅₀ of bromocriptine from 1.2 μM (without sulpiride) to 2.5 μM (with sulpiride) (P<0.05), thereby indicating a rescue effect. (f) Representative micrographs of the inhibitory effects of bromocriptine on NPC expansion when challenged with a competitive antagonist. Scale bars, 500 mm.

FIG. 13 shows that bioactive neuromodulators display a rich intra-class chemical diversity. (a) 8 of the 22 bioactive agents identified as dopamine signaling regulators. All 8 molecules are found in unique clusters when grouped based on 2D chemical fingerprint. A total of 10 different clusters were identified within the 22 agents known to act on the dopamine pathways. (b) 8 of the 12 bioactive agents identified as serotonin signaling regulators. All 8 molecules are found in unique clusters when grouped based on 2D chemical fingerprint. A total of 10 different clusters were identified within the 12 agents known to act on the serotonin pathway. P-value represents the original significance testing preformed from the screening data. Reported drug targets displayed in this figure represents curated data published in Wishart, D. S. et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 34, D668-D672 (2006) and inhouse.

FIG. 14 shows SAR analysis of adenosine and serotonin agonists. (a) SAR analysis an array of structurally similar adenosine agonist (cluster 132): CGS-21680 (54), 5′-N-Ethylcarboxamidoadenosine (55), HE-NECA (56), 2-Phenylaminoadenosine (58), 5′-N-Methyl carboxamidoadenosine (57), N6-Cyclohexyladenosine (59). (b) SAR analysis an array of structurally similar serotonin agonists (cluster 127): R(+)-UH-301 (48), S(−)-UH-301 (64), R-(+)-8-Hydroxy-DPAT (65), (±)-8-Hydroxy-DPAT (66), (±)—PPHT (67) (DRD2 agonist). “Active” agents and represents agents found to significantly suppress the number of viable cells (MTT scores) in the initial screen. “inactive” agents represent agents that were predicted to have activity (but did not) based on their structural similarities; suggesting important structural changes. Functional substitutions presumed to have positive (blue) and negative (red) effects on activity are circled.

FIG. 15 shows SAR analysis of dopamine agonists and antagonist (a) SAR present in structurally related dopamine antagonists (cluster 130). i. Perphenazine (26) ii. Fluphenazine (68) iii. Trifluoperazine (70) iv. cis-(Z)-Flupenthixol (7) v. Triflupromazine (69) vi. Propionylpromazine (72) vii. Prochlorperazine (71) (b) SAR present in structurally related dopamine agonist (cluster 84). i. Apomorphine (6) ii. R(−)-Apocodeine (63) iii. R(−)-Propylnorapomorphine (5) iv. R(−)—N-Allylnorapomorphine (62) v. R(−)-2,10,11-Trihydroxyaporphine (60) vi. R(−)-2,10,11-Trihydroxy-Npropylnoraporphine (61). All agents (unless otherwise stated) were active in the initial screen. Agents are arranged in descending order (i.=most active and vii=least active) with respect to their observed biological response. Functional substitutions presumed to have positive (blue) and negative (red) effects on activity are circled.

DETAILED DESCRIPTION OF THE INVENTION Glossary

For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

The recitation of numerical ranges by endpoints herein includes all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.” Further, it is to be understood that “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing “a NSC Modulating Agent” includes a mixture of two or more compounds. The term “about” means plus or minus 0.1 to 50%, 5-50%, or 10-40%, preferably 10-20%, more preferably 10% or 15%, of the number to which reference is being made.

The terms “subject” and “patient” are used interchangeably herein and refer to an animal including a warm-blooded animal such as a mammal, which is afflicted with or suspected of having or being pre-disposed to a condition disclosed herein. Preferably, the terms refer to a human. The terms also include domestic animals bred for food, sport, or as pets, including horses, cows, sheep, poultry, fish, pigs, cats, dogs, and zoo animals. The methods herein for use on subjects and patients contemplate prophylactic as well as curative use. Typical subjects for treatment include persons susceptible to, suffering from or that have suffered a condition disclosed herein.

The terms “administering” or “administration” refers to the process by which a therapeutically effective amount of an NSC Modulating Agent or composition contemplated herein is delivered to a patient for prevention and/or treatment purposes. Compositions are administered in accordance with good medical practices taking into account the patient's clinical condition, the site and method of administration, dosage, patient age, sex, body weight, and other factors known to physicians.

The term “pharmaceutically acceptable carrier, excipient, or vehicle” refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered. A carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition. The use of such media and agents for an active substance is well known in the art.

By “pharmaceutically acceptable salts” is meant those salts which are suitable for use in contact with the tissues of a subject or patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art and are described for example, in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66:1 The term “pharmaceutically acceptable salt(s)” includes salts of acidic or basic groups which may be present in the compounds which can be employed. In particular, pharmaceutically acceptable acid addition salts of an NSC Modulating Agent are provided. Acids which can be used to prepare the pharmaceutically acceptable acid addition salts are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, para-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts. In other aspects, pharmaceutically acceptable base addition salts of an NSC Modulating Agent are also provided. Chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts are those that form non-toxic base salts with such compounds. Suitable nontoxic base salts include, without limitation, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine (meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

The term “treating” refers to reversing, alleviating, or inhibiting the progress of a disease, or one or more symptoms of such disease, to which such term applies. Depending on the condition of the subject, the term also refers to preventing a disease, and includes preventing the onset, or preventing the symptoms associated with a disease. A treatment may be either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. Such prevention or reduction of the severity of a disease prior to affliction refers to administration of a compound or composition described herein to a subject that is not at the time of administration afflicted with the disease. “Preventing” also refers to preventing the recurrence of a disease, or of one or more symptoms associated with such disease. The terms “treatment” and “therapeutically,” refer to the act of treating, as “treating” is defined above. The purpose of prevention and intervention is to combat the disease, condition, or disorder and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.

The terms “treating” and “treatment” utilized herein in respect to a CNS tumor or primary CNS tumor refer to a situation where the severity of a symptom of a CNS tumor, including the volume of the tumor or the frequency with which any symptom or sign of the tumor is experienced by a patient, or both, is reduced, or where time to tumor progression or survival time is increased.

A “beneficial effect” refers to an effect of an NSC Modulating Agent or composition described herein that is greater than the effect without the agent or composition. The beneficial effect includes favorable pharmacological and/or therapeutic effects, and improved pharmacokinetic properties and biological activity. In another aspect, the beneficial effect is a “sustained beneficial effect” where the beneficial effect is sustained for a prolonged period of time after termination of treatment. A beneficial effect may be sustained for at least about 1 to 5 days, 2 to 7 days, 1 to 2 weeks, 1 to 4 weeks, and 1 to 6 weeks, 2 to 16 weeks, 2 weeks to 6 months or periodically following treatment. The period of time a beneficial effect is sustained may correlate with the duration and timing of the treatment. A subject may be treated continuously for about 1 to 3 days, 1 to 5 days, 2 to 7 days, 1 to 2 weeks, 1 to 4 weeks, and 1 to 6 weeks, 2 to 16 weeks, 2 weeks to 6 months or periodically.

The beneficial effect may be a statistically significant effect in terms of statistical analysis of an effect of an agent when compared to no agent. “Statistically significant” or “significantly different” effects or levels with an agent may represent levels that are higher or lower than a standard. In one embodiment, the difference may be 1.5, 2, 3, 4, or 5 times higher or lower compared with the effect obtained without the agent.

A “medicament” refers to a pharmaceutical composition suitable for administration of a pharmaceutically active compound(s) (i.e., NSC Modulating Agent) to a patient.

“Therapeutically effective amount” relates to the amount or dose of an active compound or composition described herein that will lead to one or more therapeutic effect, in particular desired beneficial effects. A therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the substance to elicit a desired response in the subject. Dosage regime may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

A “neural stem cell” refers to an undifferentiated neural cell capable of proliferation, self-maintenance, and production of differentiated functional progeny.

A “neural progenitor cell” refers to an undifferentiated cell derived from a neural stem cell, which is not itself a stem cell. Some progenitor cells can produce progeny that are capable of differentiating into more than one cell type. A progenitor cell, unlike a stem cell, has limited proliferative ability and thus does not exhibit self-maintenance. It is committed to a particular path of differentiation and will, under appropriate conditions, eventually differentiate into neurons, glia, astrocytes or oligodendrocytes. In one embodiment, the neural progenitor cells are early neural progenitor cells.

The term “neural precursor cells” refers to the progeny of neural stem cells, and thus includes both progenitor cells and daughter neural stem cells.

A “modulator” includes an “inhibitor”, “antagonist”, “stimulator”, “activator”, “enhancer” or “agonist”. An “inhibitor” or “antagonist” is defined by any molecule/compound/agent that is capable of eliciting a decrease in an activity or response (e.g., a NSC Modulating Agent that elicits a decrease in proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs). A “stimulator”, “activator”, “enhancer” or “agonist” is defined by any molecule/compound/agent that is capable of eliciting an increase in an activity or response (e.g., a NSC Modulating Agent that elicits an increase in proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs).

“NSC Modulating Agent” refers to a modulator that modulates proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells and/or NSCs. Examples of NSC Modulating Agents that modulate proliferation, differentiation and/or renewal of diseased neural precursor cells, neural progenitor cells and/or NSCs include without limitation, dopamine receptor antagonists, dopamine receptor agonists, acetylcholine receptor antagonists, NMDA receptor antagonists, opioid receptor agonists, retinoic acid receptor agonists, JAK3 antagonists, p38 MAPK antagonists, serotonin receptor agonists, or vanilloid receptor agonists. An NSC Modulating Agent may be a commercially available drug or a new formulation of a commercially available drug adapted for treating a condition disclosed herein.

A “dopamine receptor” refers to a receptor that mediates dopaminergic neurotransmission in the central nervous system and in particular members of the G protein-coupled receptor family, more particularly striatal dopamine receptors. Dopamine receptors include without limitation D1, D2, D3, D4, and D5 dopaminergic receptors.

“Dopamine receptor agonists” include natural and synthetic agents that function as specific agonists acting on dopamine receptors, in particular striatal dopamine receptors. Suitable agonists are well known in the art and readily available for use within the methods and compositions described herein. A principal class of dopamine receptor agonists for use herein includes natural and synthetic or semisynthetic ergolines derived or modeled after ergot alkyloids, for example, apomorphines and ergotamines.

Particular examples of dopamine receptor agonists include, without limitation, levodopa/carbidopa, amantadine, bromocriptine, pergolide, R(−) propylnorapomorphine, apomorphine, benserazide, lysuride, mesulergine, lisuride, lergotrile, memantine, metergoline, piribedil, tyramine, tyrosine, phenylalanine, bromocriptine mesylate, pergolide mesylate, and the like, preferably R(−) propylnorapomorphine or apomorphine.

The dopamine receptor agonist may be selected from among adrogolide, A-86929, rotigotine, NeurVex, Nolomirole, pramipexole, talipexole, CHF 1512, (−)-stepholidine, DAR-201, Diacrin/Genzyme, bromocriptine, Bupropion, LEK-8829, BAM-1110, AIT-203, NS-2330, Terguride, Aripiprazole, OPC-4392, GMC-1111, PD-148903, apomorphine HCl, PD-89211, PD-158771, cabergoline, sumanirole, PNU-14277E, POL-255, dihydrexidine, GBR-12783, quinagolide HCl, (R)-bupropion, S-32504, S-33592, SKF-80723, SKF-83959, fenoldopam, ropinirole, SKF-82958, SKF-77434, DU 127090, SLV-308, SLV 318, NeuroCRIB, SP-1037C, spheramine, Gallotrank, Preclamol, DAB-452, YM-435, BP-897, ProSavin, Etilevodopa, P63, A 68930, A 77636, Alaptide, Alentemol, CI 1007; PD 143188, BLSI, JA 116a; JA 116, Melevodopa; Levodopa methyl; CHF 1301; NSC 295453; Levomet, MR 708, PD 128483, RD 211, SKF 38393, SKF 81297, U 86170F, U 91356A, WAY 124486 and Z 15040.

A dopamine receptor agonist that acts on one or more specific dopamine receptors may be selected. For example, certain tetralins and related ergoline derivatives have been reported as centrally acting D2 dopamine receptor agonists (Wickstrom, Prog Med. Chem. 29:185-216, 1992); and 5-hydroxy-2-N,N-n-dipropylaminotetralin (5-OH-DPAT), 7-OH-DPAT and 8-OH-DPAT, have been reported as specific and selective ligands for the D3 receptors (Levesque, Proc. Natl. Acad. Sci. USA 89:8155-8159, 1992; Mulder, et al., Arch. Pharmacol 336: 494-501, 1987; and Beart, et al, Arch. Pharmacol. 336: 487-493, 1987)

Additional dopamine receptor agonists that may be useful include for example, SKF-38393 HCl (SKF), a D1 dopaminergic receptor agonist (Muralikrishnan, Brain Res. 892:241-7, 2001); ropinirole (SKF-101468) (Reaville et al., J. Pharm. Pharmacol 52:1129-35, 2000); and, ABT-431, a D1 agonist (Self et al., Ann. N Y Acad. Sci. 909:133-44, 2000). See also DeWald et al., J. Med. Chem. 33:445-450, 1990; Grol et al., J. Pharm. Pharmacol. 43:481-485, 1991; Hall et al., J. Med. Chem. 30:1879-1887, 1987; Horn et al., J. Med. Chem. 27: 1340-1343, 1984; Johansson et al., J. Med. Chem. 30: 1827-1837, 1987; Jobansson et al., Mol. Pharmacol. 30:258-269, 1986; Johansson et al., J. Med. Chem. 28:1049-1053, 1985; Johansson et al., J. Med. Chem. 30:602-611, 1987; Johansson et al., J. Org. Chem. 51: 5252-5258, 1986; Johansson et al., J. Med. Chem. 33:2925-2929, 1990; Jones et al., J. Med. Chem. 27:1607-1613; 1984; Langlois et al., Synthetic Comm. 22:1723-1734, 1992; Martin et al., J. Pharmacol. Exp. Ther. 230:569-576, 1989; Neumeyer et al., J. Med. Chem. 34:24-28, 1991; Seiler et al., Mol. Pharmacol. 22:281-289, 1982; and Sibley et al., TIPS 13: 61-68, 1992 for additional teachings regarding identification, selection, pharmacology, and production of dopamine receptor agonists and their derivatives and analogs for use within the methods and compositions described herein.

“Dopamine receptor antagonists” include natural and synthetic agents that function as specific antagonists acting on dopamine receptors, in particular striatal dopamine receptors. A dopamine receptor antagonist is generally capable of blocking, either completely or partially, the action and/or function of the receptor. Suitable antagonists are well known in the art and readily available for use within the methods and compositions described herein. Particular examples of dopamine receptor antagonists are cis-(Z) flupenthixol, perphenazine, (±) butaclamol, and alkylphosphocholines, in particular miltefosine, domperidone and pimozide, preferably butaclamol.

“NMDA receptor antagonist” refers to compounds which are capable of blocking, either completely or partially, the action and/or function of the NMDA receptor or the NMDA receptor complex. NMDA receptor antagonists block the ion channel, others act at the glycine(B) site, and still others are selective for NR2B NMDA receptor subtypes (see, inter alia, Danysz and Parsons (2002) Neurotox Res 4, 119-126 or Danysz et al (2002) Curr Pharm Des 8, 835-843). “NMDA receptor antagonists” include natural and synthetic agents that function as specific antagonists acting directly on an NMDA receptor. NMDA receptor antagonists are well known and can be selected for use herein.

An NMDA receptor antagonist to be employed preferably inhibits/blocks a human NMDA receptor(s). Human NMDA receptors have been described in the art and are also described by their protein structure and/or their encoding nucleotide sequences. Sequences for NMDA receptors may easily be obtained in current databases, like the EMBL-EBI™ database under www.ebi.ac.uk or the NCBI database under www.ncbi.nlm.nih.gy. Exemplified, non limiting NMDA receptors comprise the receptors encoded by nucleotide sequences as shown under NM 00835 and NM 00833 in the NCBI database (gene accession number).

Examples of NMDA receptor antagonists include 1-amino-alkylcyclohexanes like memantine or neramexane (MRz 2/579 or 1-amino-1,3,3,5,5-pentamethyl-cyclohexane) (see International Patent Publication No. WO 2005/009421, US Patent Publication No. 2004/0087658, U.S. Pat. No. 4,122,193; U.S. Pat. No. 4,273,774 or U.S. Pat. No. 5,061,703), 6,7-dichloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (licostinel) (ACEA 1021), gavestinel, CP-101606, Ro-25-6981, Co101244 (see Kohl (2001) Curr Med. Chem. 8, 1275-1289), eliprodi (see U.S. Pat. No. 5,547,963, International Patent Publication No. WO 97/33582, International Patent Publication No. WO 97/02823, U.S. Pat. No. 5,023,266), dizocilpine, conantokins, ifenprodil, ifenprodil tartrate, arcaine, pentamidine isethionate, L-701, 324, CGP4O1 16, LY235959, LY233053, MRZ2/576, LU73068, 4-Cl—KYN or pharmaceutically acceptable salts or prodrugs of these substances, including the hydrochloride salt of neramexane, namely 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride, and the mesylate salt of neramexane, namely 1-amino-1,3,3,5,5-pentamethyl-cyclohexane mesylate. In one embodiment, the NMDA receptor antagonist is ifenprodil, ifenprodil tartrate, memantine or neramexane.

“Acetylcholine receptor antagonists” include natural and synthetic agents that function as specific antagonists acting on acetylcholine receptor. An acetylcholine receptor antagonist is generally capable of blocking, either completely or partially, the action and/or function of the receptor. Suitable antagonists are well known in the art and readily available for use within the methods and compositions described herein. Particular examples of acetylcholine receptor antagonists are the M1 antagonists R-trihexyphenidyl, telenzepine and pirenzepine, the M3 antagonists hexahydro-sila-difenidol and p-fluorohexahydro-siladifenidol, and the M2 and M4 antagonists himbacine methoctramine, AF-DX 116 and AQ-RA 741, preferably hexahydro-sila-difenidol.

“Opioid receptor agonists” include natural and synthetic agents that function as specific agonists acting on an opioid receptor. An opioid dopamine receptor agonist is generally capable of stimulating or enhancing, either completely or partially, the action and/or function of the receptor. Suitable antagonists are well known in the art and readily available for use within the methods and compositions discussed herein. Particular examples of opioid receptor agonists are carbetapentane citrate, dextromethorphan, dextromethorphan hydrobromide, noscapine, metaphit methanesulfonate, and chlophedianol hydrochloride, preferably carbetapentane citrate.

“Retinoic acid receptor agonists” include natural and synthetic agents that function as specific agonists acting on a retinoic acid receptor. A retinoic acid receptor agonist is generally capable of stimulating or enhancing, either completely or partially, the action and/or function of the receptor. Suitable agonists are well known in the art and readily available for use within the methods and compositions provided herein. An “RAR agonist” can be either naturally occurring or a synthetic retinoid, preferably having selective activity as an agonist for RARs and high potency in antagonism of AP-1-dependent gene expression. Examples of naturally occurring retinoids with activity as RAR agonists are all-trans retinoic acid (all-trans RA) and 9-cis retinoic acid (9-cis RA), which are stereoisomers, all-trans RA being naturally converted into 9-cis RA during metabolism (J. G. Allen, et al., Pharmac. Ther. 40:1-27, 1989). Synthetically retinoids are well known in the art. For example, U.S. Pat. No. 5,234,926, discloses methods of synthesizing disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups with selective activity as RAR agonists. U.S. Pat. No. 4,326,055 discloses methods for synthesizing 5,6,7,8-tetrahydro naphthyl and indanyl stilbene derivatives with retinoid-like activity. Examples of synthetic RAR agonists that may be used are ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate and 6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinic acid (see U.S. Pat. No. 5,234,926); and p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid (see U.S. Pat. No. 4,326,055). In one aspect, the retinoic acid receptor agonist is fenretinide.

“JAK3 antagonists” include natural and synthetic agents that function as specific antagonists acting on JAK3. A JAK3 antagonist is generally capable of blocking, either completely or partially, the action and/or function of JAK3. Suitable antagonists are well known in the art and readily available for use within the methods and compositions described herein. Particular examples of JAK3 antagonists are WHI-P131 and the JAK3 inhibitors disclosed in U.S. Pat. No. 6,933,300 including without limitation 4-(4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (P131), 4-(3′-bromo-4′-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (P154), 4-(3′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline, (P180) and 4-(3′,5′-dibromo-4′-hydroxyphenyl)-6,7-dimethoxyquinazoline (P97).

“p38 MAPK antagonists” include natural and synthetic agents that function as specific antagonists acting on the p38 subfamily of MAP kinases, including p38α, p38β, p38γ, and p38δ. A p38 MAPK antagonist is generally capable of blocking, either completely or partially, the action and/or function of a MAP kinase. Suitable antagonists are well known in the art and readily available for use within the methods and compositions described herein. Particular examples of p38 MAPK antagonists are SB 202190 (Sigma Aldrich), SB203580 and PD169316 (Fu Y et al, Biochem Biophys Res Commun. 2003 Oct. 17; 310(2):391-7), and FR167653 (Nishikawa et al, Arthritis Rheum. 2003 September; 48(9):2670-81).

“Serotonin receptor agonists” include natural and synthetic agents that function as specific agonists acting on a serotonin receptor. A serotonin receptor agonist is generally capable of stimulating or enhancing, either completely or partially, the action and/or function of the receptor. Suitable agonists are well known in the art and readily available for use within the methods and compositions provided herein. Particular examples of serotonin receptor agonists are aminophenethyl-m-trifluoromethylphenyl piperazine (PAPP), 8-OH-DPAT, sumatriptan, L694247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indol-3yl]ethanamine), buspirone, alnitidan, zalospirone, ipsapirone, gepirone, zolmitriptan, risatriptan, 311C90, α-Me-5-HT, BW723C86 (1-[5(2-thienylmethoxy)-1H-3-indolyl[propan-2-amine hydrochloride), and MCPP (m-chlorophenylpiperazine).

“Vanilloid receptor agonists” include natural and synthetic agents that function as specific agonists acting on a vanilloid receptor. A vanilloid receptor agonist is generally capable of stimulating or enhancing, either completely or partially, the action and/or function of the receptor. Suitable agonists are well known in the art and readily available for use within the methods and compositions herein. Particular examples of opioid receptor agonists are dihydrocapsaicin, resiniferatoxin and other resiniferatoxin-like complex polycyclic compounds such as tinyatoxin, capsaicin and other capsaicin analogs such as dihydrocapsaicin, ovanil, anandamid, eicosinoids prostacyclin, PGE₂, 20-homovanillyl esters of diterpenes such as 12-deoxyphorbol 13-phenylacetate 20-homovanillate and mezerein 20-homovanillate (see U.S. Pat. Nos. 4,939,194; 5,021,450; and 5,232,684), analogs of capsaicins including vanillylacylamides, homovanillyl acylamides, carbamate derivatives, sulfonamide derivatives, urea derivatives, aralkylamides and thioamides, aralkyl aralkanamides, phenylacetamides and phenylacetic acid esters, olvanil (N-vanillyl-9-octadecenamide). See, e.g., U.S. Pat. No. 5,962,532; U.S. Pat. No. 5,762,963; U.S. Pat. No. 5,221,692; U.S. Pat. No. 4,313,958; U.S. Pat. No. 4,532,139; U.S. Pat. No. 4,544,668; U.S. Pat. No. 4,564,633; U.S. Pat. No. 4,544,669; and U.S. Pat. Nos. 4,493,848; 4,532,139; 4,564,633; and 4,544,668; and the agonists described in International Patent Publication No. WO 00/50387, and agonists disclosed by Hwang et al., PNAS 97 (11): 6155-6160 (2000).

The terms “dopainine receptor agonists”, “dopamine receptor antagonists”, “acetylcholine receptor antagonist”, “NMDA receptor antagonist”, “opioid receptor agonist”, “retinoic acid receptor agonist”, “JAK3 antagonist”, “p38 MAPK antagonist”, “serotonin receptor agonist”, and “vanilloid receptor agonist” as used herein also embrace chemically modified analogs, derivatives, salts and esters of the agonists/antagonists which are “pharmaceutically acceptable,” for example salts and esters that are suitable for use in contact with mucosal tissues of humans and other mammals, without undue toxicity, irritation, allergic response, and the like, and which retain activity for their intended use. Pharmaceutically acceptable salts can be prepared in situ during isolation and purification of the agonists or antagonists, or separately by reacting the free base or acid functions of the agonists or antagonists with a suitable organic acid or base. Representative acid addition salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate salts and the like. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts, and the like.

As used herein, the terms “condition” and “disease” are used interchangeably to refer to a condition or disease in a subject. “Condition” and “disease” include but are not limited to diseases or disorders where there is neurological damage or a neurological disorder.

In one aspect, the disease is a disease of the brain or central nervous system. In particular aspects utilizing NSC Modulating Agents that are antagonists or inhibitors of proliferation, differentiation and/or renewal of diseased (e.g. cancerous) neural precursor cells, neural progenitor cells and/or NSCs, the condition or disease is an abnormal growth in the brain or central nervous system, more particularly a primary CNS tumor. In an embodiment, the condition is brain or CNS cancer, more particularly a primary CNS tumor. In embodiments, the condition is a brain tumor having a genetic profile resembling that of normal and embryonic neural precursor cells. In other embodiments, the condition is a brain tumor enriched for cancer stem cells.

“Primary CNS tumor” includes a neoplasia with origins in the brain, in that the cancerous cells did not originate in another part of the body and metastasize to the brain. Examples of primary CNS tumors include, but are not limited to, gliomas, well-differentiated astrocytomas, anaplastic astrocytomas, glioblastoma multiforme, ependymomas, oligodendrogliomas, ganglioneuromas, mixed gliomas, brain stem gliomas, optic nerve gliomas, meningiomas, pineal tumors, pituitary tumors, pituitary adenomas, reactive gliosis, primitive neuroectodermal tumors, medulloblastomas, schwannomas, lymphomas, vascular tumors, and lymphomas.

In aspects utilizing NSC Modulating Agents that are agonists or stimulators of proliferation, differentiation and/or renewal of normal neural precursor cells, neural progenitor cells and/or NSCs the condition or disease is a neurological disorder including Down Syndrome, Parkinson's disease, Huntington's Chorea, pathogenic psychotic conditions, schizophrenia, neurodegenerative disorders including cognitive dysfunction and dementia (e.g., Alzheimer's disease) or central nervous system (CNS) trauma (e.g., stroke and epilepsy).

In particular aspects utilizing NSC Modulating Agents that are agonists or stimulators of proliferation, differentiation and/or renewal of normal neural precursor cells, neural progenitor cells and/or NSCs, the condition or disease is a neurological disorder including without limitation a presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesias, mania, attention deficit disorder, attention deficit hyperactivity disorder, sleep-wake disorder, chronic-fatigue syndrome, tremor, epilepsy, neuropathic pain, addiction (e.g., nicotine addiction), anxiety, dyslexia, schizophrenia, obsessive-compulsive disorder, and Tourette's syndrome.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

A pharmaceutical composition which has been adapted for administration to a subject to treat a condition or disease disclosed herein (e.g., brain or CNS tumors) is provided. In an aspect the composition is in a form such that administration to a subject results in modulation of proliferation, differentiation and/or renewal of normal or diseased (e.g. cancerous) neural precursor cells, neural progenitor cells and/or NSCs. In an embodiment, the composition is in a form such that administration to a subject results in inhibition of proliferation, differentiation and/or renewal of diseased (e.g. cancerous) neural precursor cells, neural progenitor cells and/or NSCs. In another embodiment, the composition is in a form such that administration to a subject results in stimulation of proliferation, differentiation and/or renewal of normal neural precursor cells, neural progenitor cells and/or NSCs.

Methods are provided for the prevention, treatment or intervention of a condition in a subject comprising administering an NSC Modulating Agent or a pharmaceutical composition described herein to provide a beneficial effect, more particularly a sustained beneficial effect.

In an aspect, a method is also provided for the prevention or intervention of a condition discussed herein in a subject comprising administering a therapeutically effective amount of an NSC Modulating Agent. In one aspect, a treatment or intervention is provided which provides beneficial effects, including sustained beneficial effects following treatment.

In methods providing beneficial effects, in particular statistically significant beneficial effects or sustained beneficial effects, an NSC Modulating Agent inhibits proliferation, differentiation and/or renewal of diseased neural precursor cells, neural progenitor cells and/or NSCs.

The invention relates to a method of treatment comprising administering a therapeutically effective amount of at least one NSC Modulating Agent which upon administration to a subject with symptoms of, or diagnosed brain or CNS cancer, produces beneficial effects, preferably sustained beneficial effects, manifested as decreased proliferation, differentiation and/or renewal of diseased neural precursor cells, early neural progenitor cells and/or NSCs.

In another aspect, methods are provided for treating a primary CNS tumor in a patient in need thereof by administering a composition comprising an NSC Modulating Agent in a therapeutically effective amount to decrease proliferation differentiation and/or renewal of diseased neural precursor cells, early neural progenitor cells and/or NSCs.

Also contemplated is the use of a composition comprising an NSC Modulating Agent for the preparation of a medicament. In one aspect, a therapeutically effective amount of at least one NSC Modulating Agent is used to r provide beneficial effects, preferably sustained beneficial effects, in treating a disease disclosed herein. In another aspect, the use of an NSC Modulating Agent for the preparation of a medicament for inhibiting proliferation, differentiation and/or renewal of diseased (e.g. cancerous) neural precursor cells, neural progenitor cells and/or NSCs is provided. In a further aspect, the use of an NSC Modulating Agent for the preparation of a medicament for stimulating proliferation, differentiation and/or renewal of normal neural precursor cells, neural progenitor cells and/or NSCs is provided.

The compounds, compositions, and medicaments discussed herein can be administered by any means that produce contact of the active agent(s) with the agent's sites of action in the body of a subject or patient. The compounds, compositions, and medicaments in the described dosages are administered by conventional methods including without limitation orally, intranasally, by inhalation, intraperitoneally, subcutaneously, intramuscularly, transdermally, sublingually or intravenously.

The active ingredients can be administered simultaneously or sequentially, and in any order at different points in time, to provide the desired beneficial effects. The compounds and compositions can be formulated for sustained release, for delivery locally or systemically. It lies within the capability of a skilled physician or veterinarian to select a form and route of administration that optimizes the effects of the compositions and treatments.

The compositions may be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular forms all utilizing dosage forms well known to those of ordinary skill in the pharmaceutical arts. The compositions may be administered by intranasal route via topical use of suitable intranasal vehicles, or via a transdermal route, for example using conventional transdermal skin patches. A dosage protocol for administration using a transdermal delivery system may be continuous rather than intermittent throughout the dosage regimen.

A dosage regimen will vary depending upon known factors such as the pharmacodynamic characteristics of the agents and their mode and route of administration; the species, age, sex, health, medical condition, and weight of the patient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, the route of administration, the renal and hepatic function of the patient, and the desired effect. The effective amount of a drug required to prevent, counter, or arrest progression of a condition can be readily determined by an ordinarily skilled physician or veterinarian.

A composition, medicament, or treatment may comprise a unit dosage of at least one NSC Modulating Agent. A “unit dosage” refers to a unitary i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active agents as such or a mixture with one or more solid or liquid pharmaceutical excipients, carriers, or vehicles.

In another aspect, an improved pharmaceutical composition is provided comprising therapeutically effective suboptimal amounts of a NSC Modulating Agent in a form for chronic or acute therapy of a condition disclosed herein, in particular a brain or CNS cancer.

A composition or formulation may be administered to a subject continuously or periodically.

The compositions or fractions thereof typically comprise suitable pharmaceutical diluents, excipients, vehicles, or carriers selected based on the intended form of administration, and consistent with conventional pharmaceutical practices. The carriers, vehicles etc. may be adapted to provide an additive, synergistically effective or therapeutically effective amount of the active compounds. Suitable pharmaceutical diluents, excipients, vehicles, and carriers are described in the standard text, Remington: The Science and Practice of Pharmacy (21^(st) Edition. 2005, University of the Sciences in Philadelphia (Editor), Mack Publishing Company), and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999. By way of example, for oral administration in the form of a capsule or tablet, the active components can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium, sulfate, dicalcium phosphate, mannitol, sorbital, and the like. For oral administration in a liquid form, the agents may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Suitable binders (e.g. gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes), lubricants (e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride), disintegrating agents (e.g. starch, methyl cellulose, agar, bentonite, and xanthan gum), flavoring agents, and coloring agents may also be combined in the compositions or components thereof.

In one aspect, a pharmaceutical composition has a pH from about 7 to 10.

Formulations for parenteral administration of a composition may include aqueous solutions, syrups, aqueous or oil suspensions and emulsions with edible oil such as cottonseed oil, coconut oil or peanut oil. Dispersing or suspending agents that can be used for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, and polyvinylpyrrolidone.

Compositions for parenteral administration may include sterile aqueous or non-aqueous solvents, such as water, isotonic saline, isotonic glucose solution, buffer solution, or other solvents conveniently used for parenteral administration of therapeutically active agents. A composition intended for parenteral administration may also include conventional additives such as stabilizers, buffers, or preservatives, e.g. methylhydroxybenzoate or similar additives.

In an embodiment, a solid form pharmaceutical composition is provided (e.g. tablets, capsules, powdered, or pulverized form) comprising a crystalline or amorphous NSC Modulating Agent.

In another embodiment, a liquid drug formulation is provided and comprises pharmaceutically acceptable salts of an NSC Modulating Agent, and to lyophilized drug formulations that can be reconstituted to provide suspensions that are stable and suitable for parenteral administration.

A composition described herein may be sterilized by, for example, filtration through a bacteria retaining filter, addition of sterilizing agents to the composition, irradiation of the composition, or heating the composition. Alternatively, the compounds and compositions may be provided as sterile solid preparations e.g. lyophilized powder, which are readily dissolved in sterile solvent immediately prior to use.

After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of a composition, such labeling would include amount, frequency, and method of administration.

Kits are also provided. In an aspect, a kit comprises or consists essentially of agents or compositions described herein. The kit is a package that houses a container which contains agents, a NSC Modulating Agent or composition disclosed herein, and also houses instructions for administering the agent or composition to a subject. In one aspect, a pharmaceutical pack or kit is provided comprising one or more containers filled with one or more NSC Modulating Agent or one or more ingredients of a composition described herein. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.

As there may be advantages to mixing a component of a composition described herein and a pharmaceutically acceptable carrier, excipient or vehicle near the time of use, the invention encompasses kits in which components of the compositions are packaged separately. For example, the kit can contain an active ingredient in a powdered or other dry form in, for example, a sterile vial or ampule and, in a separate container within the kit, a carrier, excipient, or vehicle, or a component of a carrier, excipient, or vehicle (in liquid or dry form). In an aspect, the kit can contain a component in a dry form, typically as a powder, often in a lyophilized form in, for example, a sterile vial or ampule and, in a separate container within the kit, a carrier, excipient, or vehicle, or a component of a carrier, excipient, or vehicle. Alternatively, the kit may contain a component in the form of a concentrated solution that is diluted prior to administration. Any of the components described herein, any of the carriers, excipients or vehicles described herein, and any combination of components and carriers, excipients or vehicles can be included in a kit.

A kit can include two or more therapeutic agents. The components can be combined with a carrier, excipient, or vehicle or packaged separately. For example, a kit can contain an NSC Modulating Agent, and, in a separate container, another therapeutic agent.

Optionally, a kit may also contain instructions for preparation or use (e.g., written instructions printed on the outer container or on a leaflet placed therein) and one or more devices to aid the preparation of the solution and/or its administration to a patient (e.g., one or a plurality of syringes, needles, filters, tape, tubing (e.g., tubing to facilitate intravenous administration) alcohol swabs and/or the Band-Aid® applicator). Compositions which are more concentrated than those administered to a subject can be prepared. Accordingly, such compositions can be included in the kits with, optionally, suitable materials (e.g., water, saline, or other physiologically acceptable solutions) for dilution. Instructions included with the kit can include, where appropriate, instructions for dilution.

In other embodiments, the kits can include pre-mixed compositions and instructions for solubilizing any precipitate that may have formed during shipping or storage. Kits containing solutions of one or more NSC Modulating Agent and one or more carriers, excipients or vehicles may also contain any of the materials mentioned above (e.g., any device to aid in preparing the composition for administration or in the administration per se). The instructions in these kits may describe suitable indications (e.g., a description of patients amenable to treatment) and instructions for administering the solution to a patient.

The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.

EXAMPLES Example 1

Small molecule high throughput screens in complex cell-based assays hold great promise for drug discovery but have not yet been widely applied to primary precursor cells (1). A library of 1,267 pharmacologically active compounds was screened against clonogenic colonies derived from murine neural stem cells (NSCs). From 160 initial hits, 12 potent and selective inhibitors of both normal and cancerous neural precursor cell proliferation and self renewal were characterized. These inhibitory compounds spanned a broad range of neurotransmission modulators, suggesting that the NSC may be anchored in a complex “ground state” in which proliferation and cell fate determination are regulated by myriad neural signaling pathways (2,3). These findings suggest that the mechanism of action of neuroactive drugs must be re-evaluated in the context of the NSC and that redeployment of clinically approved agents may afford a potent means to treat intractable CNS tumors. (4,5).

Although the candidate gene approach has been successful at uncovering vital pathways in NSC biology, to date only a small set of highly-studied networks has been sampled. Comprehensive identification of the signaling signature that regulates the neural precursor compartment is essential to define the NSC ground state. Because previous studies have demonstrated an intimate relationship between NSC self-renewal and neurosphere proliferation (13), a chemical genetic screen for inhibitors of neurosphere proliferation was undertaken in order to systematically profile the operational circuitry of the NSC (FIG. 1 c).

The following methods were employed in the study described in the Examples:

Primary Embryonic Murine Neural Stem Cell (mNSC) Isolation and Culture. Isolation and culture of primary embryonic (e14.5) mouse NSCs was performed as previously described (36). Briefly, pregnant FVB mice were sacrificed by cervical dislocation at gestational age 14.5 (E14.5) and embryonic telencephalons were dissected in artificial cerebral spinal fluid (ACSF). After mechanical dissociation with a flame-narrowed Pasteur pipette, the telencephalic tissue was then passed through a 40 μm cell strainer (Falcon) and quantified for viable cells using trypan blue exclusion. Living cells were plated at a density of 10⁶ cells/mL at 37° C. in chemically-defined neural stem cell media (37) containing 20 ng/mL⁻¹ human recombinant epidermal growth factor (EGF) (Sigma), 20 ng/mL⁻¹ basic fibroblast growth factor (bFGF) (Upstate) and 2 μg/mL⁻¹ heparin (Sigma) and fed every 2-3 days. Secondary mNSC Neurosphere Culture and Chemical Screens. Prior to chemical screens and other manipulations, the NSC fraction in culture was expanded by growing freshly dissected cells as primary neurospheres (8,38) in bulk culture (10⁶ cells/mL). After 7 days, primary neurospheres were collected and enzymatically digested for 3 minutes at 37° C. using the ACCUTASE™ reagent (Sigma) and then briefly mechanically dissociated with a 1 mL pipette. Cells were then strained and counted as above. Viable cells were plated at clonal density (20 cells/μL) in 96-well plates (Falcon) in a final volume of 100 μL and screened in singlets against the LOPAC™ library (Sigma) at a concentration of 3 μM (0.03% DMSO). On day 4, each well in the screen was supplemented with an additional 50 μL of fresh mNSC media and another aliquot of the LOPAC™ library (maintaining the final concentration of each compound at 3 μM). Secondary neurosphere cultures were then incubated for an additional 3 days (day 7) at which point the effect of each compound was assessed by quantifying the total proliferation of each well using the MTT proliferation assay. Z-score and p-values for the entire screen are listed in Table 3. Assessment of Total Neurosphere Culture Proliferation. Total neurosphere proliferation for all experiments was assessed after seven days using the Thiazolyl Blue Tetrazolium Bromide (MTT) (Sigma) calorimetric proliferation assay (5 mg/mL). Briefly, 15 μL of MTT were added to the 150 μL of media in each well and incubated at 37° C. for 4 hours. After this time, the reaction was quenched by solubilizing the cells with 100 μL of 10% SDS/0.01 M HCl. Each well was then quantified using a microplate reader (Versamax) at an optical density of 575 nm. Background plate effects (FIG. 7) occurring from the evaporation of media over the course of the experiment was estimated by:

$b_{i} = {\frac{1}{N - N_{i}^{h}}{\sum\limits_{j = 1}^{N}\; x_{i,j}^{\prime}}}$

where x′_(i,j) is the value at well i of plate j, h is the number of excluded hits that were 2 standard deviations below the mean and b_(i) represents the estimated background at each well position (39). The respective background was then subtracted from the raw MTT value measured for each point (FIG. 8). To calculate significance, the theoretical probability density function [N(1.0,0.11)] was fitted to the empirical normalized distribution obtained from the screen (FIG. 8 b). Compounds that caused optical density readings to significantly deviated from this function (P<0.01) were designated as bioactive (40). Dose-Response Curves and EC₅₀ Calculations. Potency of confirmed bioactive compounds was quantified by generating dose-response curves for mNSC under the same cell density and culture conditions described for the initial screen. Starting from initial concentrations between 300-30 μM, each compound was titrated across a series of 10 half-log dilutions. Each agent was tested in triplicate in at least three independent experiments. The average effective concentration that decreased the MTT reading by 50% (EC₅₀) after seven days was calculated by fitting the data points to the four-parameter logistic sigmoidal dose-response curve:

$Y = {{EC}_{100} + \frac{{EC}_{0} - {EC}_{100}}{1 + 10^{{\log {({{EC}_{50} - X})}}{({{Hill}\mspace{11mu} {Slope}})}}}}$

where X is the logarithm of concentration and Y is the predicted response. Curve fitting was performed with the GraphPad PRISM® Software. Assessment of the Neural Stem Cell Specific Effects of Selected Inhibitory Agents. To directly address if the identified agents and their respective pathways were specifically affecting the NSC fraction of the precursor cultures, the number of neurospheres generated from a single cell suspension of 2000, 1000, and 500 cells following chemical pretreatment were counted. Specifically, primary neurospheres were dissociated into a single cell suspension and subjected to the estimated EC₇₅ of selected agents from different neurotransmission classes for 7 days. These cultures were then taken, dissociated once again and plated in fresh media. Neurospheres (>50 μm in diameter) generated from these cultures after seven days were then used as an index of the number of NSC present in culture following treatment. Data shown represents the average of two independent experiments each containing 6 replicates. Astrocyte Screen and Neurosphere Selectivity Assessment. Selectivity of each compound for mNSC was assessed by constructing dose-response curves and EC₅₀ calculations for the normal astrocytic GFAP expressing cell line C8-D1A (ATCC), which was derived from cells from the cerebellum of an 8 day old mouse. For consistency, cell densities and feeding schedules for these cells were identical to those described in the in NSC cultures. For all experiments, astrocytes were grown in DMEM media (GIBCO) supplemented with 10% fetal bovine serum and cultured as described in the ATCC product information guide. Murine Medulloblastoma Generation and Culture. Tumor cells were isolated from the cerebellum of 16 week old patched heterozygous (ptc1^(+/−)) mice displaying ataxia. Mice were sacrificed using cervical dislocation and the cerebellum immediately removed and washed with artificial cerebrospinal fluid (ACSF). Tumors were macroscopically separated from normal tissue/blood and resuspended in 2 mL of the ACCUTASE™ reagent. The tissue was gently triturated with a flamed polished Pasture pipette and incubated at 37° C. for 5 minutes. Cells were then washed with DMEM/F12 and resuspended in the serum-free chemically defined media described above. Subsequent culture and HTS of these cells was preformed as described above for normal E14.5 NSC; data shown represents the average and standard deviation of a single experiment preformed in triplicate. Flow Cytometry. To confirm that precursor markers found in human brain tumors are also expressed in ptc1^(+/−) tumors, primary spheres were dissociated to single cell suspension using the ACCUTASE™ reagent, resuspended in 1×PBS with 0.5% BSA and 2 mM EDTA and passed through a 40 μM cell strainer. Four μL CD133-PE (eBioscience) was added to 100 μL of cell suspension and incubated for 30 min in the dark at 4° C. 4 μg/mL Propidium Iodide was added to exclude dead cells. Prominin-1 expression was assessed by the proportion of cells that were positive for expression above the levels see in the unstained control.

Results

To assess if the clonogenic neurosphere assay was suitable for high throughput screening (HTS), the Z′-factor (a measurement of HTS assay quality)(16) of neural precursor cells grown at clonal density for seven days was determined. Incorporation of the vital dye Thiazolyl Blue Tetrazolium Bromide (MTT) was used to compare proliferation of cultures grown in the presence of negative (0.03% DMSO) and positive (3 M cycloheximide) controls; the Z′-factor of this assay was 0.78, well within a suitable range for HTS (FIG. 5 a). Correlation of over 1,000 MTT values for replicate experiments scattered throughout the dynamic range of the assay revealed a Pearson correlation co-efficient of 0.981, again confirming the reliability of the assay (FIG. 5 b).

1,267 compounds in the Library of Pharmacologically Active Compounds (the LOPAC™ library, Sigma MO) were screened for inhibitors of neurosphere proliferation. 160 compounds significantly decreased MTT values from the predicted underlying distribution of the screen (P<0.01) (FIG. 6 a, Table 3). To assess if multiple agents in specific drug classes had a propensity for inhibiting neurosphere proliferation, compounds were clustered into groups of known pharmacologic action (Table 1, Table 4). Drug classes that non-specifically target essential cellular processes scored as hits in the screen, including alkylating agents, apoptosis inducers, cytoskeleton inhibitors and antibiotics. Unexpectedly, however, many agents that modulate neurotransmission in the dopamine, serotonin, opioid, glutamate, vanilloid, and other pathways potently inhibited growth of the undifferentiated population of precursor cells. Many of these agents are used in the clinical treatment of neurological disorders and are traditionally thought to act on mature CNS cell populations. Different compounds induced a variety of neurosphere phenotypes, including changes in sphere number, sphere size, and cell-cell or cell-surface adhesion properties (FIG. 2 b). This variety of differentiated states suggests that an elaborate balance of signaling pathways dictates neural precursor cell fate.

To verify hits from the primary screen, a representative sample of candidate agents from each pharmacological class were retested at the original screen concentration of 3 μM. Of the 43 candidates retested, 93% exhibited significant activity (P<0.05) when compared to vehicle control in triplicate for three independent experiments (see FIG. 6). Because other neural cell types such as astrocytes are known to express and signal through neurotransmitter receptors (17), a counter-screen was performed in a proliferating normal mouse astrocyte cell line to assess the selectivity and potency of each agent for neurosphere cultures. It was reasoned that this counter-screen would allow not only the identification of small molecules that were specific for signaling pathways present in neural precursors, but it would also help rule out non-specific cytotoxic agents. Dose response curves were performed for the 43 compounds in both neurosphere and astrocyte cultures and used to determine the effective concentration needed to decrease proliferation by 50% (EC₅₀) (FIG. 3 a-f, Table 5). A neurosphere selectivity ratio, defined as EC_(50 astocytes)/EC_(50 precursor cells), for each compound was determined and compared to that of three known non-specific inhibitors of proliferation (cycloheximide, etoposide and carboplatin; FIG. 3 a-c). Compounds that exhibited a neurosphere selectivity ratio (n.s.r.) greater than that observed in the control agents (n.s.r. >5.08) were defined as neural precursor cell-specific agents (FIG. 3 d-f, Table 2). From the focused set of 43 candidates, 12 highly potent and highly selective compounds were identified that attenuate neurosphere proliferation through a variety of different signaling pathways. Notably, the serotonin agonist PAPP (p-aminophenethyl-m-trifluoromethylphenyl piperazine) and the vanilloid receptor ligand dihydrocapsaicin were respectively 702 and 192 fold more selective for normal neural precursors than astrocyte cultures.

Neurospheres are comprised of a heterogeneous population of neural stem cells and lineage restricted progenitor cells (10). To determine if the inhibitors affected NSC self renewal, as opposed to proliferation of more committed precursor populations, the colony forming efficiency of treated neurosphere cultures was analyzed. With the exception of dihydrocapsaicin from the vanilloid class, representative compounds from each major class reduced secondary neurosphere formation upon re-culture in the absence of drug (FIG. 3 g). This result demonstrates that the inhibitors selectively targeted the NSC pool that is predominantly responsible for sphere formation.

As gene expression profiles of a variety of brain tumor subtypes resembles that of normal and embryonic neural precursor cells (118-21), agents that inhibit normal neural precursor growth might inhibit cultures of brain tumors that are enriched for cancer stem cells. Therefore the activity of the 12 most selective inhibitors of neural precursor growth were assessed against low passage (<4) neurosphere cultures of a spontaneous medulloblastoma from a heterozygous patched (ptc1^(+/−)) mouse (22). Like their normal counterparts, cancerous precursor cells isolated from the tumors of these mice grow as spheres in the absence of serum and in the presence of EGF and FGF and express the neural precursor marker prominin1 (CD133) (FIG. 4 a,b). The 12 neural precursor-specific agents also potently suppressed the proliferation of the ptc1^(+/−) medulloblastoma precursor cells (FIG. 4 c, Table 6). Notably, some of these agents were an order of magnitude more effective in inhibition of ptc1^(+/−) tumor cell growth in vitro than reported concentrations of the sonic hedgehog signaling inhibitor cyclopamine (0.5 μM versus 5 μM) (23). Pharmacologically active small molecules that inhibit normal neural precursor proliferation are thus also candidate chemotherapeutics against brain tumor stem cells.

The ex vivo and in situ manipulation of NSC for treating neurological disorders, including brain cancer, will require a global understanding of the pathways that regulate the behavior of these cells. Through a chemical genetic approach the existence of a complex functional “ground state” has been uncovered in neural stem cells, as defined operationally by the plethora of pathways that suppress neural precursor proliferation (FIG. 4 d, e). The observed sensitivity of neural precursor cells to agents from different neurotransmitter classes reveals that neural precursor cells are modulated by signaling pathways previously thought to function only in mature CNS cells. The release of NSC proliferation from the ground state may require an appropriate local environment of neurotransmitter activities (24). Recent studies on individual pathways support the notion that proliferation of different neural stem and progenitor subpopulations in vivo may be regulated by dopamine, serotonin, acetylcholine and glutamate (25-31). Moreover, neurosphere cultures have been reported to express receptors for various neurotransmitters (32). The systematic chemical genetic analysis substantially elaborates the cohort of pathways that control NSC proliferation (Table 1, Table 4) and, importantly, demonstrates the simultaneous operation of these pathways in precursor cells cultured under uniform experimental conditions. This promiscuous functional sensitivity of precursor cultures to a spectrum of neuroactive compounds supports the notion of lineage-priming in the NSC compartment, similar to that seen in hematopoietic stem cells (2).

The strong selectivity of many agents for precursor cultures and primary medulloblastoma cells suggests that the affected pathways lie high in the hierarchical organization of the NSC lineage. Furthermore, the often complete inhibition of neurosphere proliferation and the effects on secondary replating suggests that stem cells and/or very early progenitor components of the population are affected by these agents. The finding that both inhibitors and activators of specific pathways inhibit neurosphere proliferation (e.g. dopamine receptor agonists and antagonists) suggests that a complex signaling landscape dictates NSC fate (33). It is also possible that off-target effects account for these observations in neural precursors (34).

The results of this small molecule screen have important implications for current clinical practice in the treatment of neurological diseases. The unanticipated actions of well-characterized clinical agents on the neural precursor compartment may be partly or even solely responsible for the observed clinical benefits of these agents and/or the adverse side-effects that arise after prolonged therapy. Investigation of these possibilities for various neurological disorders may enable the development of novel NSC-specific or NSC-sparing approaches in the clinic.

In light of evidence that CNS tumors are maintained by cancer stem cells (5,6), which have similarities to normal neural stem cells (18), the potent and selective anti-proliferative agents identified in this study may presage a next generation of therapeutic agents in brain cancer. That the same agents can also potently suppress primary medulloblastoma sphere cultures supports this prospect. Intriguingly, a retrospective analysis of cancer incidence in Parkinson's patients revealed a significant reduction in the prevalence of brain tumors (35); it is suggested that this correlation may derive from the effect of anti-Parkinsonian drugs on the precursor cells from which brain tumors are thought to arise. If the complex neuronal precursor ground state as proposed also defines the identity of brain tumor stem cells, redeployment of pharmacologically-approved agents may well afford a potent and non-toxic means to treat often intractable CNS tumors.

Example 2

The cancer stem cell hypothesis posits that important functional analogies exist between normal neural stem cells (NSCs) and brain tumor stem cells (BTSCs). New insights into human brain tumour biology and treatment will thus likely emerge from further study of normal neural stem cells. These parallels have recently been exploited in a chemical genetic screen that identified a surprising repertoire of neurotransmission modulators that inhibit the growth of both NSC and BTSC cultures in vitro (see Example 1). Prompted by these findings, an investigation was conducted to determine whether epidemiological evidence supports a hypothesis that brain tumors might be regulated by neurotransmission pathways in vivo. Analysis of previously published retrospective studies suggests that patients with a wide variety of neuropsychiatric disorders exhibit a decrease in brain tumor incidence. This reduction may derive from the use of drugs that collaterally affect the neural stem cell compartment, and thereby limit the precursor populations that give rise to brain tumors. Standard chronic neuropharmacological interventions that have been used for decades in neuropsychiatric care are thus candidates for redeployment as low toxicity brain cancer therapeutics. This is the first application of concepts in stem cell biology to identify previously unappreciated sub-populations with reduced cancer incidence.

In adults, high grade gliomas represent at least one third of all primary brain tumors diagnosed. Even with intensive radio- and chemotherapy following surgical resection, the median survival of these patients is 9-12 months, with only 8-12% of patients surviving past 2 years [Burger, P. C., V et al Cancer 56, 1106-1111 (1985); Galanis, E. & Buckner, J. Br. J. Cancer 82, 1371-1380 (2000)]. The recent introduction of the DNA alkylating agent temozolomide, which prolongs the median survival time from 12.1 to 14.6 months [Cohen, M. H., et al., Clin. Cancer Res. 11, 6767-6771 (2005)], represents the most significant chemotherapeutic advancement in the management of gliomas in the last 30 years [Newlands, E. S., et al., Cancer Treat Rev. 23, 35-61 (1997)]. With such a grim prognosis and so few, if any, documented examples of complete remission [Stupp, R. et al. N. Engl. J. Med. 352, 987-996 (2005)], brain tumor treatment strategies must apparently shift away from traditional anti-neoplastic drug classes.

Recent evidence suggests that brain tumors are maintained by rare cancer cells with stem cell-like properties [Singh, S. K. et al. Nature 432, 396-401 (2004) and Vescovi, A. L., et al., Nat. Rev. Cancer 6, 425-436 (2006)]. Moreover, the discovery of stem cells in the postnatal brain suggests not only that normal neural stem cells (NCSs) may direct neuronal regeneration but that such cells may be the root cause of brain cancers. The inability of traditional therapeutics to eliminate rare brain tumour stem cells (BTSCs) may account for frequent therapeutic failure and uniform clinical relapse [Bao, S. et al. Nature 444, 756-760 (2006)]. The development of agents that act on BTSCs offers the prospect of more effective means to treat brain cancer. Although a number of studies suggest a role for neurotransmission pathways in NSC proliferation and/or differentiation, it is unknown if similar regulatory networks influence cancer of the brain. To substantiate this, evidence was sought that suggests that patients initially diagnosed with a variety of neuropsychiatric disorders (and hence presumed to be on chronic neuromodulatory medication) exhibited differential brain tumor incidence compared to the general population.

The analysis of historical cohorts has made it possible to identify strong correlations between many cancers and human behavior; however, the relative rarity of brain cancer and typical late-stage diagnosis hampers statistical analysis. Brain cancer is thus a disease with few known risk and preventative factors, including the potential association with extrinsic environmental modifiers such as use of neuromodulatory drugs in clinical settings. Fortunately, the differential incidence of more prevalent cancers (such as breast, skin, and lung) among neuropsychiatric patients has prompted investigation of the relationships of these co-morbidities.

Reports of brain tumor incidence in some of these studies allowed retrospective assessment of correlations between psychiatric diagnosis (and presumed neuromodulator consumption) on brain cancer risk. Published studies were identified from 2000 onwards that report patients with co-morbid neurologic or psychiatric conditions and cancer. From these, eight studies were found that reported brain cancer incidence rates following an initial neurologic or psychiatric diagnosis. In the analysis of these studies, it was assumed that patients included in the studies are on chronic neuromodulatory pharmacologic therapy. This is a valid assumption for Parkinson's disease, schizophrenia and major depression in the periods of time that the studies encompass.

Notably, Lalonde and Myslobodsky examined the association between breast cancer incidence, among 144,364 subjects previously diagnosed with Parkinson's disease (PD) [Lalonde, F. M. & Myslobodsky, M. Breast 12, 280-282 (2003)]. Within this study was the unremarked-upon correlation that PD patients experienced a 5-fold reduction (˜0.625% vs. ˜0.125%; P<0.01) in the incidence of brain tumors, as compared to a control normal population. The continuous administration of anti-Parkinsonian drugs in this cohort might have decreased NSC and/or BTSC proliferation, and thereby attenuated the cell populations that are the likely origins of cells responsible for propagating brain cancer. However, other studies that followed brain tumor incidence in patient populations presumed to be treated with psychoactive drugs revealed less conclusive correlations (See “Reported SIR” in Table 9). For example, although Lichtermann et al. [Arch. Gen. Psychiatry 58, 573-578 (2001)] also reported a reduced standardized incidence ratio (SIR) of brain tumors in schizophrenia patients (SIR=0.86), this reduction was not statistically significant. Similar non-significant reductions in brain tumor SIRs have also been noted in schizophrenic patients by others [Dalton, S. O., et al, Schizophr. Res. 75, 315-324 (2005); Goldacre, M. J., et al Br. J. Psychiatry 187, 334-338 (2005); Barak, Y., et al., Cancer 104, 2817-2821 (2005); and Grinshpoon, A., et al. 73, 333-341 (2005)]. Interestingly, other studies report an opposite and positive association between neurological diseases and brain cancer incidence [Dalton, S. O., et al. Am. J. Epidemiol. 155, 1088-1095 (2002); Olsen, J. H. et al. 92, 201-205 (2005); and Carney, C. P., et al Psychosom. Med. 66, 735-743 (2004)]. These studies, however, reveal a characteristic bimodal temporal pattern of brain tumor incidence. For example, in a study of patients with depression, although a remarkably high SIR of 3.27 for brain tumour incidence was observed within the first year following diagnosis, this value steadily decreased to 0.84 after 10 or more years from initial diagnosis (FIG. 9) [Dalton, S. O., et al. Am. J. Epidemiol. 155, 1088-1095 (2002)]. A similar bimodal phenomenon has been reported in Parkinson's disease patients: despite an initial increase in brain tumor incidence (SIR=1.32), incidence decreased substantially (SIR=0.85) five or more years after initial diagnosis [Olsen, J. H. et al. 92, 201-205 (2005)]. A third study that cited an elevated overall brain tumor incidence rate (SIR>2.00) in patients with mental illnesses similarly noted that median time to brain tumor diagnosis following psychiatric hospitalization was only 18 months [Carney, C. P., et al Psychosom. Med. 66, 735-743 (2004)]. The apparent initial increase in brain tumor incidence in these patients might in fact derive from occult pre-existing tumours associated with psychiatric manifestations. The failure to account for an initial disproportionate increase in brain tumor incidence in such patients may have obscured an important underlying relationship between psychiatric disease, its treatment, and brain tumor incidence. To account for this possible masking effect, the previous studies were re-analyzed after exclusion of brain tumors associated with the initial psychiatric or neurologic diagnosis (cancers <2 years from initial hospitalization) and indeed found a much more consistent negative correlation between psychiatric diagnosis and cancer incidence (See “Revised SIR” in Table 9). Although the low number of patients in each individual study precludes statistical significance, the pooled data sufficiently raises statistical power to reveal a significant decrease in brain tumor incidence in patients with psychiatric disorders (SIR=0.8, P=0.01, Comprehensive Meta-Analysis software). This result suggests that a wide array of neuromodulators may protect against brain cancer; such effects might derive from inhibition of the cell compartment that may give rise to brain tumors, i.e., neural stem cells, as observed in vitro [Examples 1 and 3].

Recent model system studies lend strong support to a BTSC neuromodulation hypothesis. Notably, the mGlu4 glutamate receptor agonist PHCCC has to be shown to attenuate medulloblastoma formation in vivo in mice [Iacovelli, L. et al. J. Neurosci. 26, 8388-8397 (2006)]. The generality of this phenomenon is suggested by the finding that a wide variety of psychoactive drugs known to act on diverse neurotransmission pathways inhibit both normal and cancerous neural precursor cell proliferation in vitro [Examples 1 and 3]. Intriguingly, the most potent anti-BTSC agents identified in these in vitro screens included the clinically prescribed dopamine agonist apomorphine [Hagell, P. & Odin, P. J. Neurosci. Nurs. 33, 21-28 (2001)] and the glutamate antagonist ifenprodil [Caillard, P., et al., Angiology 44, 552-560 (1993)]. Beyond the potential clinical implications for the long term use of neuropsychiatric agents acting on normal neural precursors, the cohort of well-tolerated neuropharmacological agents used in standard psychiatric practice offer the prospect of rapid redeployment in clinical trials for late stage brain cancers.

Example 3

To profile the signaling network of primary cultures of neural precursor cells (NPCs), 1,267 compounds were screened in the library of pharmacologically active compounds (the LOPAC™ library) for inhibitors of neurosphere proliferation, as measured by incorporation of the vital dye thiazolyl blue tetrazolium bromide (MTT) (FIG. 1 a and FIG. 2 a and Table 10). A Z¢ factor (16) of 0.78 and a Pearson correlation coefficient of 0.981 for replicate screens indicated that the assay was reliable. 160 compounds that significantly inhibited neurosphere proliferation (P<0.01) were clustered into groups of known pharmacologic action (Table 10 and Table 4). Known cytotoxic compounds that target essential cellular processes predictably scored as hits in the screen. Unexpectedly, however, many agents that modulate neurotransmission in the dopamine, serotonin, opioid, glutamate, vanilloid and other pathways potently inhibited growth of NPCs. Many of these agents are used in the clinical treatment of neurological disorders and are traditionally thought to act on mature central nervous system (CNS) cell populations. These compounds induced a variety of neurosphere phenotypes, including changes in sphere number, sphere size, and cell-cell or cell-surface adhesion properties, which suggests that an elaborate balance of these signaling pathways dictates NPC fate (FIG. 2 b).

To verify hits from the primary screen, 43 representative candidates were retested at the original screen concentration of 3 mM; of these, 40 (93%) showed significant activity (Po0.05) (Table 8). Because other neural cell types express and signal through a number of neurotransmitter receptors (42), the selectivity and potency of each agent were assessed for a normal mouse astrocyte cell line versus NPCs. Dose-response curves were generated for 28 compounds in both neurosphere and astrocyte cultures and used to determine the effective concentration needed to decrease proliferation by 50% (EC₅₀) (FIG. 10 a-f and Table 8). A neurosphere selectivity ratio, defined as EC₅₀ (astrocytes)/EC₅₀ (neurospheres), was determined for each compound and compared with that of known nonspecific inhibitors of proliferation (FIG. 10 a-c). Compounds that had a neurosphere selectivity ratio greater than that observed in these control agents (45.08) were defined as NPC-specific agents (FIG. 10 d-f and Table 2); 12 of the compounds tested showed high selectivity for NPCs. Notably, the serotonin agonist p-aminophenethyl-m-trifluoromethylphenyl piperazine (PAPP, 14) and the vanilloid receptor ligand dihydrocapsaicin were respectively 702- and 192-fold more selective for normal NPCs than for astrocyte cultures.

Neurospheres are comprised of a heterogeneous population of NSCs and lineage-restricted progenitor cells. To determine whether the inhibitors affected NSC self-renewal, as opposed to proliferation of more committed precursor populations, the higher order colony-forming efficiency of treated neurosphere cultures was analyzed. With the exception of dihydrocapsaicin, representative compounds from the main neurotransmission classes significantly reduced higher order neurosphere formation upon re-culture in the absence of drug (FIG. 10 g). The various inhibitors therefore seem to target the neural precursor pool that is predominantly responsible for sphere formation.

To further delineate the mechanism through which neuromodulatory agents impede expansion of NPCs in culture, timecourse analyses were performed for both cell viability and apoptosis. Unlike etoposide (FIG. 11 a) and cycloheximide (data not shown), which have immediate effects on cell proliferation and viability, the neurotransmission modulators PAPP and ifenprodil decreased viable cell numbers only after 2 d post-treatment (FIG. 11 a). Similar delayed-onset effects were observed for butaclamol, p-fluoro-hexahydrosila-difenidol (p-FHHSiD, 8) and carbetapentane (data not shown). Consistently, caspase-3 and caspase-7 concentrations were unchanged after 12 h of PAPP and ifenprodil treatment, but increased significantly (Po0.001) after 2 d of drug treatment (FIG. 1 b). This increase in the apoptotic response of treated cells occurred at concentrations of drugs that did not abolish the initial proliferation or viability of these cells (FIG. 11 c). Finally, expression of the immature NPC marker nestin was substantially decreased after treatment for 2 d with ifenprodil (FIG. 11 d) and PAPP (data not shown). These results suggest that appropriate neurotransmission signaling is required to maintain NSC proliferation, survival and identity.

As gene expression profiles of brain tumors resemble those of normal and embryonic NPCs (18-21), agents that inhibit normal neural precursor growth may also inhibit cultures of brain tumors that are enriched for cancer stem cells (41, 7, 18) Therefore the activity of a subset of NPC-specific inhibitors was assessed against low-passage (<4) neurosphere cultures derived from spontaneously formed medulloblastomas in heterozygous patched (Ptch1^(+/−)) and Ptch1^(+/−)Trp53^(−/−) mice²². Like their normal counterparts, cancerous NPCs from these tumors grow as spheres in serum-free culture and express the neural precursor marker prominin1 (CD133) (FIG. 12 a,b). The NPC-specific agents also potently suppressed the proliferation of both Ptch1+/− and Ptch1+/− Trp53−/− medulloblastoma precursor cell populations (FIG. 12 c and Table 2). Notably, some of these agents were an order of magnitude more effective in the inhibition of tumor cell growth in vitro than the hedgehog signaling inhibitor cyclopamine (23). The expansion of normal human NPCs and human glioblastoma cells was also inhibited by neuromodulators (Table 9). For example, PAPP and ifenprodil had EC₅₀ values comparable to those of commonly used nonspecific brain tumor chemotherapeutic drugs, such as carboplatin and etoposide. Re-deployment of well-tolerated pharmacologically active agents may thus afford a new generation of chemotherapeutic agents specific for brain tumor stem cells.

As even well-characterized agents may exert biological effects through off-target pathways (34), it was verified that a number of the known receptors for various agents are indeed expressed in both normal and tumor NPCs. The dopamine (DRD2), acetylcholine (M3), NMDA (NR1) and serotonin (5HT-1A) receptors were present in primary and secondary normal mouse neurosphere cultures and Ptch1+/− tumor neurosphere cultures, as determined by RT-PCR (FIG. 12 d). In addition, pharmacological inhibitors were used as a means to assess whether the growth inhibition caused by the dopamine class of neuromodulators depends on transmission through a known receptor.

In one example, (±)-sulpride (34), a D2 dopamine receptor antagonist, was able to competitively rescue the inhibitory effects of the D2 and D3 dopamine receptor agonist bromocriptine (24), as judged by both colony formation (FIG. 12 e,f) and MTT values (data not shown). To further assess the potential for off-target effects of neuromodulators in other classes, the 160 bioactive agents from the primary screen were clustered based on their chemical structures (Table 10). This analysis demonstrated substantial chemical structural diversity within each of the different neuromodulator classes. For example, the 22 bioactive dopamine agents identified in the screen spanned 10 different structural motif clusters; similarly, the 12 active serotonergic agents covered 10 different chemical clusters (FIG. 13). The observed sensitivity of NPCs to these structurally diverse agents is thus likely to arise through effects on known neurotransmission receptors, as opposed to some unknown coincident target. The ex vivo and in situ manipulation of NSCs for treating neurological disorders, including brain cancer, will require an understanding of the global signaling network that regulates NSC behavior.

Through a chemical genetic approach the existence of a complex functional ‘ground state’, was uncovered whereby NSC proliferation and self-renewal is regulated by numerous signaling pathways (FIG. 4 d,e). Importantly, this cohort includes many neurotransmission pathways previously thought to function only in mature cells of the CNS. Therefore, NSC proliferation and self-renewal requires an appropriate local environment of neurotransmitter activities, which may be provided by a basal level of autocrine feedback from more committed cells within the neurosphere or even the NSC itself. Indeed, recent studies on individual pathways support the notion that proliferation of different progenitor subpopulations in vivo may respond to dopamine, serotonin, acetylcholine and glutamate (24). Notably, the chemical genetic profile demonstrates the simultaneous operation of these pathways in NPCs cultured under uniform experimental conditions. This sensitivity of NPC cultures to a spectrum of neuroactive compounds also supports the notion of lineage priming in the NSC compartment, similar to that seen in hematopoietic stem cells (2).

Though the precursor subpopulations targeted by each inhibitor identified in the screen have yet to be definitively identified, the strong selectivity of many agents for NPCs and primary brain tumor cells suggests that the affected pathways lie high in the hierarchical organization of the neuronal lineage. Indeed, the often complete inhibition of neurosphere proliferation and the effects on secondary replating suggest that stem cells and/or very early progenitor components of the population are affected by these agents. The finding that both inhibitors and activators of specific pathways inhibit neurosphere proliferation (for example, dopamine receptor agonists and antagonists) suggests that a complex signaling landscape dictates NSC fate (33). The pro-proliferative culture conditions used in the neurosphere assay may have biased the assay against identification of significant numbers of small molecules that stimulate proliferation. A small-molecule activator of embryonic stem cell proliferation has recently been identified (43), which suggests that analogous screens may succeed in identifying activators of NPC proliferation. The unanticipated actions of well-characterized clinical agents on NPCs may account in whole or in part for the observed clinical benefits of these agents and/or the adverse side effects that arise after prolonged therapy. Effective in vivo concentrations of the anti-Parkinsonian drug apomorphine reach 6-7 μM (44), which is substantially higher than doses that affect NPCs in vitro. Thus the regulation of NSC proliferation by neurotransmitters may also dictate how the CNS is wired both during development and in the adult brain (45). Recent evidence suggests that appropriate GABA stimulation of NPCs is required for the proper integration of neurons in the adult hippocampus (46). Through structure-activity analysis, we also identified specific chemical substitutions that are important for the bioactivity of these agents in our in vitro system (FIGS. 14 and 15). Such modifications to the core chemical structure of many clinically used agents may afford a way to regulate the potentially therapeutic or harmful effects these drugs have on NPCs.

In light of the evidence that CNS tumors are maintained by cancer stem cells (41,5), which have similarities to normal NSCsm (18), the potent and selective antiproliferative agents identified in this study may presage a new generation of therapeutic agents in brain cancer. Notably, a retrospective analysis of cancer incidence in individuals with Parkinson disease revealed a significant reduction in the incidence of brain tumors relative to the expected incidence in the general population (35); this correlation may derive from the effect of anti-Parkinsonian drugs on the NPCs from which brain tumors are thought to arise. As the complex NSC ground state is likely to at least in part define the identity of brain tumor stem cells, re-deployment of pharmacologically approved neuroactive agents may provide an immediate and nontoxic means to treat often intractable CNS tumors.

Methods

Primary embryonic mouse NSC isolation and culture. Isolation and culture of primary embryonic (e14.5) mouse NSCs was performed as previously described in chemically defined NSC medium (37) containing 20 ng mL⁻¹ human recombinant epidermal growth factor (Sigma), 20 ng mL⁻¹ basic fibroblast growth factor (Upstate) and 2 μg mL⁻¹ heparin (Sigma). Cells were fed every 2-3 d (36). Secondary mouse NSC neurosphere culture and chemical screens. Before chemical screens and other manipulations, the NSC fraction in culture was expanded by growing freshly dissected cells as primary neurospheres (8) in bulk culture (10⁶ cells mL⁻¹). After 7 d, primary neurospheres were collected and enzymatically digested for 3 min at 37° C. using the ACCUTASE™ reagent (Sigma), mechanically dissociated with a 1-mL pipette and passed through a cell strainer (Falcon). Viable cells were plated at low cell densities (20 cells μl⁻¹) in 96-well plates (Falcon) in a final volume of 100 μL and screened in singlets against the LOPAC™ library (Sigma) at a concentration of 3 μM (0.03% DMSO). On day 4, each well in the screen was supplemented with an additional 50 mL of fresh mouse NSC medium and another aliquot of the LOPAC™ library (maintaining the final concentration of each compound at 3 μM). Secondary neurosphere cultures were then incubated for an additional 3 d (until day 7), at which point the effect of each compound was assessed by quantifying the total proliferation of each well using the incorporation of the vital dye MTT (Sigma) as previously described (4). Statistical analysis for chemical screen. Background plate effects occurring from the evaporation of medium over the course of the experiment were estimated by:

$b_{i} = {\frac{1}{N - N_{i}^{h}}{\sum\limits_{j = 1}^{N}\; x_{i,j}^{\prime}}}$

where x′_(i,j) is the value at well i of plate j, Nh_(i) ^(h) is the number of excluded hits or outliers that were 2 s.d. below the mean, N is the total number of plates in the screen, and b_(i) is the estimated background at each well position (39). The respective background was then subtracted from the raw MTT value measured for each point. To calculate significance (z score and P value), the theoretical probability density function N(1.0, 0.11) was fitted to the empirical normalized distribution obtained from the screen. Compounds that caused optical density readings to significantly deviate from this predicted underlying distribution function (P<0.01) were designated as bioactive (40). Dose-response curves and EC₅₀ calculations. Potency of confirmed bioactive compounds was quantified by generating dose-response curves for mouse NSC under the same cell density and culture conditions described for the initial screen. Starting from initial concentrations between 300 and 30 μM, each compound was titrated across a series of ten half-log dilutions. Each agent was tested in triplicate in at least three independent experiments. EC₅₀ values for each agent were calculated by fitting the data points to the four-parameter logistic sigmoidal dose-response curve:

$Y = {{EC}_{100} + \frac{{EC}_{0} - {EC}_{100}}{1 + 10^{{\log {({{EC}_{50} - X})}}{({{Hill}\mspace{11mu} {Slope}})}}}}$

where X is the logarithm of concentration and Y is the predicted response. Curve fitting was performed with GraphPad PRISMS software (GraphPad Software, Inc.).

The present invention is not to be limited in scope by the specific embodiments described herein, since such embodiments are intended as but single illustrations of one aspect of the invention and any functionally equivalent embodiments are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

All publications, patents and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. All publications, patents and patent applications mentioned herein are incorporated herein by reference for the purpose of describing and disclosing the methods etc. which are reported therein which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

TABLE 1 HTS bioactive pharmacological classes Active Total % Active Class^(†) Agents^(‡) Agents in Class Cytotoxic^(§) 38 114 33 Biochemistry 6 46 13 Cannabinoid 1 6 17 Cholinergic 8 77 10 Cyclic Nucleotides 4 31 13 Dopamine 22 113 20 Glutamate 9 88 10 Intracellular Ca²⁺ 2 7 29 Ion Pump 3 16 19 Lipid 1 9 11 Na⁺ Channel 3 17 18 Nitric Oxide 5 37 14 Opioid 6 27 22 P2 Receptor 2 14 14 Phosphorylation 9 93 10 Serotonin 12 83 14 Vanilloid 2 5 40 Entire Screen 160 1267  13^(¥) ^(†)Includes all classes with a “% Active in Class” of at least 10%. ^(‡)Only includes inhibitors ^(§)Includes: antibiotics, apoptosis, cell cycle, cell stress, cytoskeleton, and DNA ^(¥)Frequency of whole screen

TABLE 2 Highly potent and highly selective compounds identified by HTS of neurospheres Ptch1^(+/−) Ptch1^(+/−) Trp53^(−/−) Neurosphere Astrocyte Neurosphere neurosphere neurosphere Name Action Target Selectivity EC₅₀ (μM) EC₅₀ (μM) selectivity EC₅₀ (μM)^(b) EC₅₀ (μM)^(b) Controls Cycloheximide (1) Inhibitor Protein synthesis 60S ribosome 0.142 0.071 0.50 0.042 0.054 Etoposide (2) Inhibitor Topoisomerase Topo II 0.340 0.433 1.28 0.208 n.t. Carboplatin (3) Intercalator DNA n.a. 0.489 2.453 5.08 0.196 n.t. Selected hits^(a) (±) Butaclamol (4) Antagonist Dopamine receptor D2 > D1 0.785 12.34 15.7 0.751 2.533 (R)-(−)- Agonist Dopamine receptor D2 0.351 8.230 23.4 0.199 n.t. Propylnorapomorphine (5) (R)-(−)-Apomorphine (6) Agonist Dopamine receptor n.a. 0.350 10.19 29.1 0.168 0.683 cis-(Z)-Flupenthixol (7) Antagonist Dopamine receptor n.a. 0.199 1.182 5.93 0.187 n.t. p-F-HHSiD (8) Antagonist Acetylcholine M3 > M1 > M2 0.441 5.815 13.2 1.125 1.373 receptor Ifenprodil (9) Antagonist NMDA receptor Polyamine site 0.616 11.06 17.9 0.451 0.807 Carbetapentane (10) Agonist Opioid receptor Sigma 1 0.756 28.16 37.3 2.083 2.040 Fenretinide (11) Agonist Retinoic acid n.a. 0.334 2.399 7.18 0.204 n.t. receptor WHI-P131 (12) Antagonist JAK3 n.a. 2.346 n.d. >10 1.525 n.t. SB 202190 (13) Antagonist p38 MAPK n.a. 8.063 64.8 8.04 3.006 n.t. PAPP (14) Agonist Serotonin receptor 5-HT1A 0.031 21.82 702 0.169 0.097 Dihydrocapsaicin (15) Agonist Vanilloid receptor VR1 0.218 41.83 192 0.020 0.651 Cyclopamine (16) Antagonist Smoothened n.t. n.t. n.a. 1.00  13.44  ^(a)Compounds listed represent confirmed hits with high selectivity for NPCs (neurosphere selectivity >5). ^(b)Ptch1^(+/−) and Ptch1^(+/−) Trp53^(−/−) neurosphere cultures were derived from mouse cerebeller tumor samples. n.a., not applicable; n.d., not determined at highest tested dose (30 μM); n.t., not tested.

TABLE 3 Product Name Z Score P Value Class L-745,870 hydrochloride −11.273568 8.86E−30 Dopamine NS 521 oxalate −11.273568 8.86E−30 Glutamate Pentamidine isethionate −11.273568 8.86E−30 Glutamate Rotenone −11.273568 8.86E−30 Cell Stress Taxol −11.273568 8.86E−30 Cytoskeleton and ECM Apomorphine hydrochloride hemihydrate −11.273568 8.86E−30 Dopamine Amsacrine hydrochloride −11.273568 8.86E−30 DNA Repair Brefeldin A from Penicillium brefeldianum −11.273568 8.86E−30 Cytoskeleton and ECM Cytosine-1-beta-D-arabinofuranoside hydrochloride −11.273568 8.86E−30 DNA Metabolism Dequalinium analog, C-14 linker −11.273568 8.86E−30 Phosphorylation (+)-Butaclamol hydrochloride −11.273568 8.86E−30 Dopamine GBR-12935 dihydrochloride −11.273568 8.86E−30 Dopamine Idarubicin −11.273568 8.86E−30 DNA Metabolism ML-7 −11.273568 8.86E−30 Phosphorylation Purvalanol A −11.234146 1.39E−29 Phosphorylation Podophyllotoxin −11.146914 3.71E−29 Cytoskeleton and ECM N,N,N-trimethyl-1-(4-trans-stilbenoxy)-2-propylammonium iodide −11.127221 4.62E−29 Cholinergic (B1)-7-Hydroxy-DPAT hydrobromide −11.102218 6.12E−29 Dopamine Etoposide −11.10168 6.16E−29 Apoptosis Perphenazine −11.064721 9.30E−29 Dopamine NG-Hydroxy-L-arginine acetate −10.957625 3.05E−28 Nitric Oxide GBR-12909 dihydrochloride −10.898733 5.84E−28 Dopamine Vincristine sulfate −10.792318 1.87E−27 Cytoskeleton and ECM Colchicine −10.753322 2.86E−27 Cytoskeleton and ECM PAPP −10.727538 3.78E−27 Serotonin Chelerythrine chloride −10.670736 6.98E−27 Phosphorylation MG 624 −10.65959 7.86E−27 Cholinergic Tamoxifen citrate −10.643209 9.38E−27 Phosphorylation Hexamethonium dichloride −10.634291 1.03E−26 Cholinergic Emetine dihydrochloride hydrate −10.632537 1.05E−26 Apoptosis Ro 25-6981 hydrochloride −10.524254 3.34E−26 Glutamate beta-Lapachone −10.428163 9.22E−26 Apoptosis 2,3-Dimethoxy-1,4-naphthoquinone −10.39849 1.26E−25 Cell Stress 2-Methylthioadenosine diphosphate trisodium −10.359444 1.90E−25 P2 Receptor Mitoxantrone −10.205238 9.39E−25 DNA Metabolism Methotrexate −10.20279 9.63E−25 DNA Metabolism Fluphenazine dihydrochloride −10.196835 1.02E−24 Dopamine Naloxone hydrochloride −10.136773 1.90E−24 Opioid Diphenyleneiodonium chloride −10.067553 3.84E−24 Nitric Oxide Sanguinarine chloride −10.007525 7.06E−24 Ion Pump Dihydrocapsaicin −10.002879 7.40E−24 Vanilloid Ancitabine hydrochloride −9.9514465 1.24E−23 DNA Metabolism Arecaidine propargyl ester hydrobromide −9.931444 1.52E−23 Cholinergic R(−)-Apocodeine hydrochloride −9.8651075 2.95E−23 Dopamine Aminopterin −9.7829747 6.66E−23 Antibiotic Oligomycin A −9.7309305 1.11E−22 Antibiotic Quinacrine dihydrochloride −9.7123126 1.34E−22 Neurotransmission 4′-Chloro-3-alpha-(diphenylmethoxy)tropane hydrochloride −9.6720309 1.98E−22 Dopamine (S)-(+)-Camptothecin −9.6697698 2.03E−22 Apoptosis Sobuzoxane −9.6000064 4.00E−22 Gene Regulation Thapsigargin −9.5587077 5.96E−22 Intracellular Calcium Dequalinium dichloride −9.5400125 7.14E−22 K+ Channel Vinblastine sulfate salt −9.3963618 2.82E−21 Cytoskeleton and ECM XK469 −9.3551196 4.18E−21 Apoptosis ML-9 −9.3219716 5.71E−21 Phosphorylation Trifluoperazine dihydrochloride −9.305347 6.68E−21 Dopamine 3-Tropanyl-3,5-dichlorobenzoate −9.2724882 9.09E−21 Serotonin Raloxifene hydrochloride −9.222082 1.46E−20 Hormone L-687,384 hydrochloride −9.1556538 2.70E−20 Opioid CGP-74514A hydrochloride −9.1170189 3.86E−20 Phosphorylation alpha-Guanidinoglutaric acid −9.0407549 7.78E−20 Nitric Oxide N-Vanillylnonanamide −9.0288161 8.68E−20 Vanilloid U-74389G maleate −8.9415104 1.92E−19 Cell Stress Ganciclovir −8.9391761 1.96E−19 Cell Cycle Ifenprodil tartrate −8.9040193 2.69E−19 Glutamate cis-(Z)-Flupenthixol dihydrochloride −8.8224805 5.60E−19 Dopamine Iodoacetamide −8.7062214 1.57E−18 Biochemistry (−)Amethopterin −8.704359 1.60E−18 DNA Metabolism Calmidazolium chloride −8.5823395 4.65E−18 Intracellular Calcium Ellipticine −8.3212021 4.35E−17 Cell Cycle R(−)-Propylnorapomorphine hydrochloride −8.2743401 6.46E−17 Dopamine Metolazone −8.1125047 2.48E−16 Ion Pump Carbetapentane citrate −8.0209588 5.25E−16 Opioid Azathioprine −7.9126948 1.26E−15 P2 Receptor R(−)-N-Allylnorapomorphine hydrobromide −7.8390562 2.27E−15 Dopamine 5-Fluorouracil −7.7492672 4.62E−15 Cell Cycle 3-Methoxy-morphanin hydrochloride −7.7143362 6.08E−15 Glutamate Methoctramine tetrahydrochloride −7.0117942 1.18E−12 Cholinergic 2-(alpha-Naphthoyl)ethyltrimethylammonium iodide −6.7623855 6.79E−12 Cholinergic 3-Amino-1-propanesulfonic acid sodium −6.6910884 1.11E−11 GABA Mevastatin −6.2782013 1.71E−10 Antibiotic Carboplatin −6.2035622 2.76E−10 DNA Retinoic acid p-hydroxyanilide −6.013426 9.08E−10 Cell Cycle (B1)-Butaclamol hydrochloride −5.9339136 1.48E−09 Dopamine SB 204070 hydrochloride −5.8860023 1.98E−09 Serotonin S-(−)-Eticlopride hydrochloride −5.1577465 1.25E−07 Dopamine 3′-Azido-3′-deoxythymidine −5.0229615 2.54E−07 Immune System Chlorprothixene hydrochloride −5.0075345 2.76E−07 Dopamine Metaphit methanesulfonate −4.9672663 3.40E−07 Opioid SB 224289 hydrochloride −4.7857097 8.52E−07 Serotonin Triamterene −4.6424998 1.72E−06 Na+ Channel N-Acetylprocainamide hydrochloride −4.5574345 2.59E−06 Na+ Channel Guanidinoethyl disulfide dihydrobromide −4.5207865 3.08E−06 Nitric Oxide SKF 96365 −4.4967357 3.45E−06 Ca2+ Channel R(−)-Denopamine −4.4857956 3.63E−06 Adrenoceptor Metergoline −4.3419185 7.06E−06 Serotonin Disopyramide −4.1788419 1.46E−05 Na+ Channel (+)-Brompheniramine maleate −3.9756943 3.51E−05 Histamine Cephalexin hydrate −3.9664324 3.65E−05 Antibiotic DL-alpha-Methyl-p-tyrosine −3.9081784 4.65E−05 Neurotransmission Melphalan −3.907414 4.66E−05 DNA Metabolism CNS-1102 −3.7824639 7.76E−05 Glutamate Benztropine mesylate −3.7491883 8.87E−05 Cholinergic (B1)-Brompheniramine maleate −3.5302827 0.0002076 Histamine Actinonin −3.501397 0.0002314 Biochemistry Protoporphyrin IX disodium −3.4407749 0.00029 Cyclic Nucleotides (+)-cis-Dioxolane iodide −3.4020249 0.0003344 Cholinergic Indomethacin morpholinylamide −3.397557 0.00034 Cannabinoid Ketanserin tartrate −3.3253093 0.0004416 Serotonin Cephalosporin C zinc salt −3.3091048 0.000468 Antibiotic R(−)-2,10,11-Trihydroxyaporphine hybrobromide −3.3089272 0.0004683 Dopamine Methoxamine hydrochloride −3.255451 0.0005661 Adrenoceptor Chlorothiazide −3.1649704 0.0007755 Biochemistry Hydrocortisone −3.0490238 0.0011479 Hormone 7,7-Dimethyl-(5Z,8Z)-eicosadienoic acid −3.0454142 0.0011618 Lipid Cefaclor −3.0087895 0.0013115 Antibiotic Daidzein −2.9308316 0.0016903 Cell Cycle Prazosin hydrochloride −2.9017416 0.0018555 Adrenoceptor Z-L-Phe chloromethyl ketone −2.901083 0.0018594 Biochemistry N6-Cyclohexyladenosine −2.8830026 0.0019695 Adenosine SB 415286 −2.8700993 0.0020517 Phosphorylation (B1) trans-U-50488 methanesulfonate −2.833112 0.0023049 Opioid Isoliquiritigenin −2.8170739 0.0024232 Cyclic Nucleotides Niclosamide −2.784072 0.0026841 Antibiotic BRL 52537 hydrochloride −2.7605861 0.0028849 Neurotransmission R(−)-2,10,11-Trihydroxy-N-propylnoraporphine hydrobromide −2.744256 0.0030324 Dopamine Oxymetazoline hydrochloride −2.7197914 0.0032662 Adrenoceptor S(−)-UH-301 hydrochloride −2.7057206 0.0034078 Serotonin 1-Phenylbiguanide −2.6893106 0.00358 Serotonin NS 2028 −2.6836419 0.0036413 Cyclic Nucleotides SDZ-205,557 hydrochloride −2.6806511 0.003674 Serotonin Betaine hydrochloride −2.6682884 0.0038119 Biochemistry 6-Methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b] indole −2.6610326 0.0038951 Neurotransmission Pergolide methanesulfonate −2.656684 0.0039457 Dopamine Bepridil hydrochloride −2.6553943 0.0039608 Ca2+ Channel (−)-Sulpiride −2.6474564 0.004055 Dopamine Trazodone hydrochloride −2.6437716 0.0040994 Serotonin R-(+)-7-Hydroxy-DPAT hydrobromide −2.5903598 0.0047938 Dopamine 5′-N-Ethylcarboxamidoadenosine −2.5867918 0.0048437 Adenosine 5′-N-Methyl carboxamidoadenosine −2.5824426 0.0049052 Adenosine 3′,4′-Dichlorobenzamil −2.5808785 0.0049275 Ion Pump Cefazolin sodium −2.5795106 0.004947 Antibiotic CGS-12066A maleate −2.5753256 0.0050073 Serotonin m-Iodobenzylguanidine hemisulfate −2.5641032 0.0051721 Apoptosis SB 216763 −2.5420251 0.0055106 Phosphorylation R(+)-UH-301 hydrochloride −2.5168671 0.0059202 Serotonin 1-(2-Chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane −2.5077494 0.0060751 Hormone Zaprinast −2.5059482 0.0061062 Cyclic Nucleotides HE-NECA −2.5037672 0.0061439 Adenosine Noscapine hydrchloride −2.4554145 0.0070361 Opioid Dubinidine −2.4370692 0.0074034 Anticonvulsant Quinolinic acid −2.4191885 0.0077776 Glutamate 1-Aminocyclopropanecarboxylic acid hydrochloride −2.4013395 0.0081676 Glutamate Nimesulide −2.3951538 0.0083067 Prostaglandin (B1)-AMT hydrochloride −2.3661687 0.0089866 Nitric Oxide 2-Chloro-2-deoxy-D-glucose −2.3643801 0.0090301 Biochemistry Efaroxan hydrochloride −2.3380161 0.0096932 Imidazoline L-2-aminoadipic acid −2.3335424 0.0098098 Glutamate Ritodrine hydrochloride −2.3317783 0.0098562 Adrenoceptor 3-Aminopropylphosphonic acid −2.3313919 0.0098664 GABA Tyrphostin AG 34 −2.3191864 0.0101925 Phosphorylation S-(−)-Carbidopa −2.3143606 0.010324 Biochemistry Quercetin dihydrate −2.3024758 0.0106542 Cyclic Nucleotides SB 204741 −2.2992889 0.0107443 Serotonin cis-(B1)-8-OH-PBZI hydrobromide −2.2973336 0.0107999 Dopamine Praziquantel −2.2959636 0.010839 Antibiotic Corticosterone −2.2852893 0.0111479 Hormone Cefsulodin sodium salt hydrate −2.2766421 0.0114038 Antibiotic Tyrphostin AG 494 −2.2753482 0.0114425 Phosphorylation (B1)-6-Chloro-PB hydrobromide −2.2671332 0.011691 Dopamine Gabaculine hydrochloride −2.2563811 0.0120234 GABA (B1)-2,3-Dichloro-alpha-methylbenzylamine hydrochloride −2.2508783 0.0121966 Neurotransmission cis-Azetidine-2,4-dicarboxylic acid −2.2508387 0.0121979 Glutamate WB-4101 hydrochloride −2.2469819 0.0123206 Adrenoceptor Acetohexamide −2.2399587 0.0125468 Hormone (+)-Nicotine (+)-di-p-toluoyl tartrate −2.232955 0.012776 Cholinergic Isoguvacine hydrochloride −2.2200937 0.0132062 GABA Cortisone 21-acetate −2.2178586 0.0132822 Hormone Morin −2.2158114 0.0133522 Cell Stress R(+)-3PPP hydrochloride −2.2129185 0.0134516 Dopamine Serotonin hydrochloride −2.1965835 0.0140251 Serotonin Ro 8-4304 −2.1881143 0.0143306 Glutamate Bumetanide −2.1822656 0.014545 Ion Pump Ro 16-6491 hydrochloride −2.1810515 0.0145898 Neurotransmission 6-Aminohexanoic acid −2.179453 0.014649 Immune System 1-Allyl-3,7-dimethyl-8-p-sulfophenylxanthine −2.1783219 0.014691 Adenosine Mesulergine hydrochloride −2.1600214 0.0153855 Dopamine p-MPPF dihydrochloride −2.1595489 0.0154038 Serotonin TTNPB −2.1577952 0.0154719 Transcription (E)-4-amino-2-butenoic acid −2.1488314 0.0158239 GABA D-ribofuranosylbenzimidazole −2.143935 0.016019 Transcription Alprenolol hydrochloride −2.1429898 0.016057 Adrenoceptor (E)-5-(2-Bromovinyl)-2′-deoxyuridine −2.1233283 0.0168632 Immune System Pinacidil −2.116539 0.0171495 K+ Channel (B1)-Chlorpheniramine maleate −2.1163839 0.0171561 Histamine Fenofibrate −2.1155765 0.0171904 Transcription N6-Cyclopentyl-9-methyladenine −2.111923 0.0173465 Adenosine Mecamylamine hydrochloride −2.107644 0.0175309 Cholinergic Ranolazine dihydrochloride −2.103503 0.0177109 Lipid Lorglumide sodium −2.0918704 0.0182251 Cholecystokinin Rolipram −2.0912266 0.0182539 Cyclic Nucleotides 4-Imidazolemethanol hydrochloride −2.076595 0.0189195 Histamine PPNDS tetrasodium −2.066969 0.0193685 P2 Receptor U-101958 maleate −2.0647776 0.019472 Dopamine O-(Carboxymethyl)hydroxylamine hemihydrochloride −2.0584119 0.0197753 Biochemistry Pyrocatechol −2.0530659 0.0200331 Cell Cycle 3-Phenylpropargylamine hydrochloride −2.0432437 0.0205142 Dopamine Clemastine fumarate −2.0227881 0.0215475 Histamine R(−)-N6-(2-Phenylisopropyl)adenosine −2.0227607 0.0215489 Adenosine T-1032 −2.0203758 0.0216722 Cyclic Nucleotides DM 235 −2.0192498 0.0217306 Nootropic TCPOBOP −2.0077453 0.0223352 Transcription R(+)-Terguride −2.0044262 0.0225122 Dopamine Budesonide −1.9941208 0.0230694 Hormone Metoclopramide hydrochloride −1.9921723 0.0231761 Dopamine SP600125 −1.9856473 0.0235362 Phosphorylation Mifepristone −1.9702729 0.0244035 Hormone (B1)-Vesamicol hydrochloride −1.9674995 0.0245628 Cholinergic Niflumic acid −1.957802 0.0251266 Prostaglandin Acetamide −1.9401968 0.0261779 Biochemistry Succinylcholine chloride −1.9304248 0.0267771 Cholinergic Quinidine sulfate −1.9299053 0.0268093 Na+ Channel SKF-525A hydrochloride −1.927618 0.0269513 Multi-Drug Resistance (B1)-PPHT hydrochloride −1.9154974 0.0277145 Dopamine Proglumide −1.9073728 0.0282362 Cholecystokinin IMID-4F hydrochloride −1.9058093 0.0283375 K+ Channel Guanabenz acetate −1.9057108 0.0283439 Adrenoceptor (B1)-Muscarine chloride −1.9052038 0.0283768 Cholinergic CNQX disodium −1.9037516 0.0284713 Glutamate Thiothixene hydrochloride −1.8991787 0.0287705 Dopamine (B1)-3-(3,4-dihydroxyphenyl)-2-methyl-DL-alanine −1.8936993 0.0291325 Neurotransmission 2′,3′-didehydro-3′-deoxythymidine −1.8781951 0.0301772 Immune System (−)-Tetramisole hydrochloride −1.8662258 0.0310049 Phosphorylation GYKI 52466 hydrochloride −1.863546 0.0311927 Glutamate Doxazosin mesylate −1.8613755 0.0313456 Adrenoceptor N-Methyl-D-aspartic acid −1.8603889 0.0314153 Glutamate Citalopram hydrobromide −1.8575581 0.0316159 Serotonin (−)-Bicuculline methbromide, 1(S), 9(R) −1.8420868 0.0327312 GABA Fenoterol hydrobromide −1.8408571 0.0328213 Adrenoceptor Loratadine −1.8228962 0.0341596 Histamine Triflupromazine hydrochloride −1.8204023 0.0343489 Dopamine (B1)-Vanillylmandelic acid −1.8112351 0.0350522 Adrenoceptor 2,3-Butanedione monoxime −1.8102985 0.0351248 K+ Channel AL-8810 −1.8055248 0.0354963 Prostaglandin Cyproterone acetate −1.8034569 0.0356582 Hormone L-alpha-Methyl-p-tyrosine −1.8000599 0.0359256 Neurotransmission (B1)-Normetanephrine hydrochloride −1.7963521 0.0362193 Adrenoceptor Carisoprodol −1.794693 0.0363513 Neurotransmission Dihydro-beta-erythroidine hydrobromide −1.7884178 0.0368543 Cholinergic Diacylglycerol kinase inhibitor I −1.7818091 0.0373902 Phosphorylation Buspirone hydrochloride −1.7754735 0.0379099 Serotonin Tulobuterol hydrochloride −1.7667466 0.0386353 Adrenoceptor SIB 1757 −1.7523223 0.0398592 Glutamate S-Methyl-L-thiocitrulline acetate −1.7510795 0.0399661 Nitric Oxide Rauwolscine hydrochloride −1.7473494 0.0402884 Adrenoceptor Tyrphostin A9 −1.7464939 0.0403626 Phosphorylation Clofibrate −1.7375097 0.0411486 Lipid NCS-382 −1.7333038 0.0415208 GABA N,N-Dipropyl-5-carboxamidotryptamine maleate −1.730004 0.0418148 Serotonin BRL 37344 sodium −1.7246038 0.0422994 Adrenoceptor Naphazoline hydrochloride −1.7242327 0.0423329 Adrenoceptor Pempidine tartrate −1.7188055 0.0428249 Cholinergic BP 897 −1.7150002 0.0431726 Dopamine E-64 −1.708761 0.0437476 Biochemistry 5′-(N-Cyclopropyl)carboxamidoadenosine −1.7011833 0.0444543 Adenosine SB 222200 −1.6945866 0.0450769 Tachykinin WB 64 −1.6833761 0.0461512 Cholinergic ATPO −1.6800087 0.0464778 Glutamate 3-Bromo-7-nitroindazole −1.6799458 0.0464839 Nitric Oxide Salbutamol −1.6779642 0.046677 Adrenoceptor NBQX disodium −1.6747884 0.0469879 Glutamate 5-Aminovaleric acid hydrochloride −1.6700597 0.0474538 GABA OXA-22 iodide −1.6660744 0.0478493 Cholinergic 5,5-Dimethyl-1-pyrroline-N-oxide −1.6658221 0.0478744 Cell Stress 6-Chloromelatonin −1.6590916 0.0485487 Melatonin Yohimbine hydrochloride −1.6564033 0.0488201 Adrenoceptor (B1)-Ibotenic acid −1.649771 0.0494949 Glutamate S-Nitroso-N-acetylpenicillamine −1.6450464 0.0499801 Nitric Oxide 2,3-Butanedione −1.6415063 0.0503462 Cytoskeleton and ECM SC 19220 −1.6402237 0.0504793 Prostaglandin Pentoxifylline −1.6370526 0.0508097 Cyclic Nucleotides IC 261 −1.6304637 0.0515018 Phosphorylation Karakoline −1.6253205 0.0520471 Cholinergic 2-Hydroxysaclofen −1.624107 0.0521765 GABA Trifluperidol hydrochloride −1.6214132 0.0524645 Dopamine N-Acetyl-L-Cysteine −1.6210885 0.0524993 Glutamate Pyrazinecarboxamide −1.6171791 0.0529198 Antibiotic (B1)-CGP-12177A hydrochloride −1.6114253 0.0535435 Adrenoceptor N-Phenylanthranilic acid −1.6103679 0.0536588 Cl− Channel Nitrendipine −1.6096413 0.0537381 Ca2+ Channel Tyrphostin AG 527 −1.6074748 0.0539751 Phosphorylation Tyrphostin AG 879 −1.6068612 0.0540424 Phosphorylation S-Ethylisothiourea hydrobromide −1.5993298 0.0548737 Nitric Oxide (B1)-SKF 38393, N-allyl-, hydrobromide −1.5895709 0.0559658 Dopamine Propionylpromazine hydrochloride −1.5842258 0.0565712 Dopamine 1-(4-Chlorobenzyl)-5-methoxy-2-methylindole-3-acetic acid −1.5842122 0.0565727 Multi-Drug Resistance H-8 dihydrochloride −1.582792 0.0567344 Phosphorylation Decamethonium dibromide −1.5718137 0.0579969 Cholinergic p-Benzoquinone −1.5713686 0.0580485 DNA Repair Ouabain −1.5679492 0.0584465 Ion Pump (B1)-Octopamine hydrochloride −1.5674371 0.0585063 Adrenoceptor Quinelorane dihydroechloride −1.5670037 0.0585569 Dopamine (−)-Quinpirole hydrochloride −1.5653999 0.0587446 Dopamine Kenpaullone −1.5549547 0.0599784 Phosphorylation MK-886 −1.5492409 0.0606619 Leukotriene SR 2640 −1.5478816 0.0608254 Leukotriene (+)-Pilocarpine hydrochloride −1.547825 0.0608322 Cholinergic 10-(alpha-Diethylaminopropionyl)-phenothiazine hydrochloride −1.5445928 0.0612224 Biochemistry Aminophylline ethylenediamine −1.5370027 0.0621463 Adenosine Phenelzine sulfate −1.5362935 0.0622332 Neurotransmission Propantheline bromide −1.5337772 0.0625422 Cholinergic 3-Tropanyl-indole-3-carboxylate hydrochloride −1.5275718 0.0633094 Serotonin Domperidone −1.5246276 0.063676 Dopamine PD 168,077 maleate −1.5158641 0.0647769 Dopamine 4-Aminopyridine −1.5155783 0.064813 K+ Channel Phenoxybenzamine hydrochloride −1.5122144 0.0652397 Adrenoceptor Flecainide acetate −1.4984719 0.0670053 Na+ Channel Chlorzoxazone −1.496158 0.0673062 Nitric Oxide Hexahydro-sila-difenidol hydrochloride, p-fluoro analog −1.4916183 0.0678996 Cholinergic R(−)-Isoproterenol (+)-bitartrate −1.4852187 0.0687429 Adrenoceptor Pirfenidone −1.4819638 0.069175 Immune System Histamine dihydrochloride −1.4762679 0.069936 Histamine Histamine, R(−)-alpha-methyl-, dihydrochloride −1.4694515 0.0708552 Histamine 13-cis-retinoic acid −1.4690859 0.0709047 Transcription L-733,060 hydrochloride −1.4652604 0.0714249 Tachykinin Aminobenztropine −1.4551121 0.0728191 Cholinergic Idazoxan hydrochloride −1.4475909 0.0738658 Imidazoline Quipazine dimaleate −1.4441402 0.0743498 Serotonin Tranylcypromine hydrochloride −1.4406843 0.0748369 Neurotransmission Cortexolone maleate −1.4340948 0.0757726 Dopamine L-Histidine hydrochloride −1.4212033 0.0776288 Histamine SB-366791 −1.4192379 0.0779148 Vanilloid L(−)-Norepinephrine bitartrate −1.4177813 0.0781273 Adrenoceptor R(−)-Me5 −1.4142867 0.0786389 Na+ Channel 7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4- −1.412018 0.0789723 Phosphorylation ylamine NG-Nitro-L-arginine methyl ester hydrochloride −1.4106378 0.0791757 Nitric Oxide (B1)-Methoxyverapamil hydrochloride −1.4065891 0.0797746 Ca2+ Channel Semicarbazide hydrochloride −1.4048769 0.080029 Neurotransmission Harmane −1.4028297 0.0803338 Imidazoline Phosphomycin disodium −1.4016291 0.080513 Antibiotic SR 57227A −1.4000539 0.0807486 Serotonin 5-azacytidine −1.3976868 0.0811036 DNA Metabolism Theobromine −1.3917931 0.0819925 Adenosine beta-Chloro-L-alanine hydrochloride −1.3900717 0.0822536 Biochemistry Diacylglycerol Kinase Inhibitor II −1.3898874 0.0822815 Phosphorylation NG-Monomethyl-L-arginine acetate −1.385845 0.0828971 Nitric Oxide Nylidrin hydrochloride −1.3754281 0.0844994 Adrenoceptor Cinnarizine −1.3747128 0.0846103 Ca2+ Channel N{circumflex over ( )}G, N{circumflex over ( )}G-Dimethylarginine hydrochloride −1.3726345 0.084933 Nitric Oxide 2′,3′-dideoxycytidine −1.3665696 0.0858801 Immune System SB 206553 hydrochloride −1.365122 0.0861073 Serotonin N-Bromoacetamide −1.3615557 0.0866691 Na+ Channel Sulfaphenazole −1.3615444 0.0866709 Multi-Drug Resistance SKF 83959 hydrobromide −1.3570686 0.0873797 Dopamine Aniracetam −1.3545038 0.0877879 Glutamate 7-Nitroindazole −1.3486346 0.0887272 Nitric Oxide Dipropyldopamine hydrobromide −1.3457188 0.0891966 Dopamine Guvacine hydrochloride −1.3454867 0.089234 GABA (B1)-DOI hydrochloride −1.3446475 0.0893695 Serotonin N-Methyl-1-deoxynojirimycin −1.3354425 0.0908658 Biochemistry Forskolin −1.3305552 0.0916677 Cyclic Nucleotides Ciprofibrate −1.3259385 0.09243 Transcription Methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate −1.3258027 0.0924525 Benzodiazepine 3-Morpholinosydnonimine hydrochloride −1.3237029 0.0928009 Nitric Oxide N6-2-(4-Aminophenyl)ethyladenosine −1.322839 0.0929445 Adenosine Luteolin −1.3226701 0.0929726 Cell Stress Altretamine −1.3219924 0.0930853 DNA Metabolism (−)-Perillic acid −1.3205658 0.0933231 G protein Tyrphostin AG 808 −1.3154937 0.094172 Phosphorylation Fluoxetine hydrochloride −1.3114178 0.0948583 Serotonin 5-Hydroxyindolacetic acid −1.3011987 0.0965952 Serotonin Thiolactomycin −1.2996027 0.0968686 Antibiotic S(−)-p-Bromotetramisole oxalate −1.2954735 0.0975785 Phosphorylation alpha,beta-Methylene adenosine 5′-triphosphate dilithium −1.2895624 0.0986013 P2 Receptor 4-Aminobenzamidine dihydrochloride −1.2867142 0.099097 Biochemistry Captopril −1.2850992 0.0993788 Neurotransmission B-HT 933 dihydrochloride −1.2803089 0.1002183 Adrenoceptor DBO-83 −1.2793912 0.1003797 Cholinergic (+)-Chlorpheniramine maleate −1.2718073 0.1017208 Histamine rac-2-Ethoxy-3-hexadecanamido-1-propylphosphocholine −1.2689544 0.1022287 Phosphorylation Mexiletene hydrochloride −1.2587311 0.1040637 Na+ Channel GYKI 52895 −1.2580442 0.1041879 Dopamine Phenylephrine hydrochloride −1.2567788 0.1044169 Adrenoceptor 2-(2-Aminoethyl)isothiourea dihydrobromide −1.251316 0.1054096 Nitric Oxide Norcantharidin −1.2508813 0.1054889 Phosphorylation Tyrphostin AG 537 −1.2486744 0.1058921 Phosphorylation MRS 2179 −1.2460372 0.1063754 P2 Receptor N-(3,3-Diphenylpropyl)glycinamide −1.2431187 0.106912 Glutamate D-Cycloserine −1.2400354 0.1074811 Glutamate Trimethoprim −1.2297472 0.1093959 Antibiotic CGS-21680 hydrochloride −1.2250915 0.1102704 Adenosine SR 59230A oxalate −1.2215096 0.1109466 Adrenoceptor Aminoguanidine hemisulfate −1.2193731 0.1113513 Nitric Oxide N-Methyldopamine hydrochloride −1.2189696 0.1114279 Dopamine LY-294,002 hydrochloride −1.2168097 0.1118383 Phosphorylation Acyclovir −1.214559 0.1122672 Immune System 8-(3-Chlorostyryl)caffeine −1.2143358 0.1123098 Adenosine Pilocarpine nitrate −1.213028 0.1125596 Cholinergic U-73122 −1.1943557 0.1161694 Lipid Ribavirin −1.1942136 0.1161972 Cell Cycle Minoxidil −1.1893439 0.1171522 K+ Channel Adenosine 3′,5′-cyclic monophosphate −1.1884072 0.1173365 Phosphorylation REV 5901 −1.1843894 0.1181295 Leukotriene L-750,667 trihydrochloride −1.1839463 0.1182172 Dopamine 1,4-PBIT dihydrobromide −1.1793121 0.119137 Nitric Oxide O6-benzylguanine −1.1766492 0.1196678 DNA Repair S(+)-PD 128,907 hydrochloride −1.1736494 0.1202677 Dopamine 6-Fluoronorepinephrine hydrochloride −1.1680109 0.1214012 Adrenoceptor Ketoprofen −1.1637674 0.1222592 Prostaglandin Monastrol −1.1620964 0.1225982 Cell Cycle TEPI hydrochloride −1.1557919 0.1238831 Nitric Oxide L-allylglycine −1.1551253 0.1240196 Biochemistry Endothall −1.1434024 0.1264358 Phosphorylation Meloxicam sodium −1.1395873 0.1272291 Prostaglandin MDL 28170 −1.1386183 0.1274312 Cell Cycle SB 202190 −1.1244198 0.1304175 Phosphorylation S(−)-Pindolol −1.1219961 0.1309321 Serotonin 3,4-Dichloroisocoumarin −1.119752 0.1314097 Biochemistry Tetraisopropyl pyrophosphoramide −1.1141073 0.1326166 Biochemistry rac-2-Ethoxy-3-octadecanamido-1-propylphosphocholine −1.1124056 0.1329819 Phosphorylation (B1)-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol −1.1085022 0.1338225 Sphingolipid hydrochloride SB 269970 hydrochloride −1.0998336 0.1357023 Serotonin FPL 64176 −1.0989013 0.1359056 Ca2+ Channel NSC 95397 −1.0984826 0.1359969 Phosphorylation Labetalol hydrochloride −1.0972055 0.1362758 Adrenoceptor CGP-13501 −1.0960408 0.1365305 GABA Cefotaxime sodium −1.0959989 0.1365396 Antibiotic Nortriptyline hydrochloride −1.0953265 0.1366868 Adrenoceptor Lamotrigine −1.0947705 0.1368086 Anticonvulsant Cinoxacin −1.0946117 0.1368434 Antibiotic 3-n-Propylxanthine −1.0936716 0.1370495 Adenosine IB-MECA −1.0890621 0.1380633 Adenosine cis-4-Aminocrotonic acid −1.0875529 0.1383963 GABA CB34 −1.0812753 0.1397873 Benzodiazepine GR 127935 hydrochloride −1.0805988 0.1399378 Serotonin LY-278,584 maleate −1.0738961 0.1414346 Serotonin 2,6-Diamino-4-pyrimidinone −1.0718915 0.1418844 Phosphorylation CB 1954 −1.0701772 0.1422698 DNA LE 300 −1.0698515 0.1423431 Dopamine (B1)-Baclofen −1.0691346 0.1425045 GABA N-Acetyl-5-hydroxytryptamine −1.0604318 0.1444741 Melatonin 1,1-Dimethyl-4-phenyl-piperazinium iodide −1.0571671 0.1452177 Cholinergic Benzamil hydrochloride −1.0541202 0.1459139 Ion Pump (R,R)-cis-Diethyl tetrahydro-2,8-chrysenediol −1.0529189 0.1461891 Hormone CX 546 −1.0499852 0.1468625 Glutamate (B1)-2-Amino-5-phosphonopentanoic acid −1.0451757 0.1479709 Glutamate Amoxapine −1.0413683 0.1488523 Adrenoceptor R(+)-Lisuride hydrogen maleate −1.0405352 0.1490457 Dopamine 3-aminobenzamide −1.0343557 0.1504849 Apoptosis Riluzole −1.0325771 0.1509009 Glutamate Reserpine −1.0232137 0.1531034 Serotonin Carcinine dihydrochloride −1.0232013 0.1531064 Cell Stress DL-Buthionine-[S,R]-sulfoximine −1.0219135 0.1534109 Multi-Drug Resistance Metaproterenol hemisulfate −1.0217093 0.1534593 Adrenoceptor 9-Amino-1,2,3,4-tetrahydroacridine hydrochloride −1.0210782 0.1536087 Cholinergic (B1)-2-Amino-7-phosphonoheptanoic acid −1.0198203 0.1539069 Glutamate Moxisylyte hydrochloride −1.0177704 0.1543935 Adrenoceptor Doxepin hydrochloride −1.0124523 0.1556609 Adrenoceptor L-741,626 −1.0093889 0.1563941 Dopamine 8-Bromo-cGMP sodium −1.004759 0.1575065 Cyclic Nucleotides CR 2249 −1.0018822 0.1582002 Glutamate GW7647 −0.992319 0.160521 Transcription Imiloxan hydrochloride −0.9878844 0.1616046 Adrenoceptor 2-methoxyestradiol −0.9832797 0.1627349 Hormone Daphnetin −0.9798216 0.1635871 Phosphorylation Cyclophosphamide monohydrate −0.9757597 0.1645918 DNA Trequinsin hydrochloride −0.9708618 0.1658085 Cyclic Nucleotides Propafenone hydrochloride −0.9673008 0.1666969 K+ Channel Felodipine −0.9658091 0.1670699 Ca2+ Channel S(−)-Pindolol −0.9652109 0.1672196 Adrenergic SR-95531 −0.9574371 0.1691734 GABA 1-benzoyl-5-methoxy-2-methylindole-3-acetic acid −0.9550434 0.1697779 Multi-Drug Resistance Albuterol hemisulfate −0.9490313 0.1713024 Adrenoceptor Chlormezanone −0.9465197 0.1719418 Neurotransmission L-N5-(1-Iminoethyl)ornithine hydrochloride −0.9338543 0.1751895 Nitric Oxide Pentylenetetrazole −0.9273972 0.1768602 Neurotransmission N-(4-Aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride −0.922864 0.178039 Intracellular Calcium Imidazole-4-acetic acid hydrochloride −0.9222582 0.1781969 GABA Tyrphostin 51 −0.917695 0.1793893 Phosphorylation Zonisamide sodium −0.9169252 0.1795909 Anticonvulsant Gallamine triethiodide −0.9155672 0.179947 Cholinergic Palmitoylethanolamide −0.913421 0.1805106 Cannabinoid Myricetin −0.9113314 0.1810604 Phosphorylation Lithium Chloride −0.9112667 0.1810774 Neurotransmission Agroclavine −0.9109378 0.1811641 Dopamine Cyclothiazide −0.9069625 0.1822133 Glutamate L-Canavanine sulfate −0.9023537 0.1834345 Nitric Oxide L-alpha-Methyl DOPA −0.8969902 0.1848621 Biochemistry D-609 potassium −0.8963774 0.1850256 Lipid BWB70C −0.893238 0.1858649 Leukotriene AC 915 oxalate −0.8902927 0.1866544 Opioid Phosphonoacetic acid −0.8884961 0.187137 DNA Promazine hydrochloride −0.8881652 0.187226 Dopamine 1,10-Phenanthroline monohydrate −0.8855339 0.1879344 Biochemistry loxoprofen −0.8833347 0.1885277 Prostaglandin Atropine methyl bromide −0.8715579 0.1917248 Cholinergic Retinoic acid −0.8656792 0.1933331 Apoptosis Prochlorperazine dimaleate −0.8601515 0.1948528 Dopamine Nimodipine −0.8541979 0.1964977 Ca2+ Channel SIB 1893 −0.8479837 0.1982235 Glutamate Chloro-IB-MECA −0.8471487 0.1984561 Adenosine 1-Methylimidazole −0.8469251 0.1985184 Prostaglandin (−)-Scopolamine methyl bromide −0.8468313 0.1985446 Cholinergic Clomipramine hydrochloride −0.8438525 0.1993759 Serotonin Tyrphostin 23 −0.8396096 0.2005636 Phosphorylation Formoterol −0.8379228 0.201037 Adrenoceptor (+)-Hydrastine −0.836196 0.2015223 GABA L-765,314 −0.8307837 0.2030479 Adrenoceptor Glipizide −0.8295042 0.2034096 K+ Channel Ceramide −0.826672 0.2042115 Phosphorylation Hexamethonium bromide −0.8198763 0.2061433 Cholinergic (B1)-Sotalol hydrochloride −0.8130085 0.2081066 Adrenoceptor S-(+)-Fluoxetine hydrochloride −0.8087781 0.2093214 Serotonin 5alpha-Pregnan-3alpha-ol-11,20-dione −0.8078192 0.2095973 GABA CPCCOEt −0.8067663 0.2099006 Glutamate Edrophonium chloride −0.8063734 0.2100138 Cholinergic Amiloride hydrochloride −0.7992459 0.2120739 Na+ Channel N6-Benzyl-5′-N-ethylcarboxamidoadenosine −0.7976302 0.2125426 Adenosine Dextromethorphan hydrobromide monohydrate −0.7931617 0.2138418 Glutamate 4-Hydroxybenzhydrazide −0.7887714 0.2151228 Biochemistry Epibestatin hydrochloride −0.7868693 0.2156792 Biochemistry Methylergonovine maleate −0.7845802 0.2163499 Dopamine N6-Cyclopentyladenosine −0.7838855 0.2165536 Adenosine Urapidil, 5-Methyl- −0.7831488 0.2167699 Adrenoceptor alpha-Methyl-5-hydroxytryptamine maleate −0.7795622 0.2178243 Serotonin Dihydroergotamine methanesulfonate −0.7794889 0.2178459 Serotonin GR-89696 fumarate −0.7787503 0.2180634 Opioid Amiprilose hydrochloride −0.7782638 0.2182068 Immune System 2-Methylthioadenosine triphosphate tetrasodium −0.7763488 0.2187715 P2 Receptor 3-Isobutyl-1-methylxanthine −0.7739684 0.2194747 Adenosine Dihydroergocristine methanesulfonate −0.7729718 0.2197695 Dopamine Putrescine dihydrochloride −0.7689496 0.2209616 Glutamate S(−)-Timolol maleate −0.7674804 0.221398 Adrenoceptor SKF 91488 dihydrochloride −0.7659952 0.2218396 Histamine erythro-9-(2-Hydroxy-3-nonyl)adenine hydrochloride −0.7655619 0.2219685 Adenosine VER-3323 hemifumarate salt −0.7613872 0.2232129 Serotonin Sodium Taurocholate −0.7603721 0.2235161 Multi-Drug Resistance Iofetamine hydrochloride −0.7588266 0.2239781 Neurotransmission Fexofenadine hydrochloride −0.7572355 0.2244544 Histamine (S)-(−)-propafenone hydrochloride −0.7523778 0.2259119 Adrenoceptor 1-Amino-1-cyclohexanecarboxylic acid hydrochloride −0.7494958 0.2267792 Neurotransmission Loxapine succinate −0.7476915 0.2273231 Dopamine (−)-Scopolamine hydrobromide −0.7415125 0.2291914 Cholinergic Haloperidol −0.7399244 0.2296729 Dopamine I-OMe-Tyrphostin AG 538 −0.7369215 0.230585 Phosphorylation SKF 97541 hydrochloride −0.7355176 0.2310122 GABA 5-Nitro-2-(3-phenylpropylamino)benzoic acid −0.7342619 0.2313946 Cl− Channel S(+)-Ibuprofen −0.7334592 0.2316392 Prostaglandin Choline bromide −0.7300479 0.2326804 Cholinergic U-69593 −0.727828 0.2333594 Opioid Dipyridamole −0.7266604 0.233717 Adenosine Ketorolac tris salt −0.7255889 0.2340454 Prostaglandin Parthenolide −0.7238191 0.2345884 Serotonin Indatraline hydrochloride −0.7236172 0.2346504 Dopamine (B1)-Nipecotic acid −0.7215396 0.2352888 GABA Clotrimazole −0.71583 0.2370482 K+ Channel p-Fluoro-L-phenylalanine −0.7022606 0.2412583 Neurotransmission (B1)-gamma-Vinyl GABA −0.7009701 0.2416608 GABA Oxotremorine methiodide −0.7001827 0.2419066 Cholinergic Ritanserin −0.6956745 0.2433164 Serotonin 4-Androstene-3,17-dione −0.6917159 0.2445579 Hormone R-(+)-8-Hydroxy-DPAT hydrobromide −0.6915933 0.2445964 Serotonin HA-100 −0.6892375 0.2453369 Phosphorylation Lidocaine N-methyl hydrochloride −0.6827508 0.2473822 Na+ Channel Tyrphostin AG 555 −0.6812093 0.2478695 Phosphorylation (R)-(+)-WIN 55,212-2 mesylate −0.6806866 0.2480349 Cannabinnoid 1,7-Dimethylxanthine −0.6622605 0.2539022 Adenosine SU 5416 −0.6621561 0.2539356 Phosphorylation Seglitide −0.6620168 0.2539802 Somatostatin L-Hyoscyamine −0.661048 0.2542908 Cholinergic BMY 7378 dihydrochloride −0.6588459 0.2549974 Serotonin (B1)-Atenolol −0.65828 0.2551791 Adrenoceptor Amantadine hydrochloride −0.6531247 0.2568379 Dopamine Nimustine hydrochloride −0.6523971 0.2570725 DNA Bethanechol chloride −0.6493048 0.2580707 Cholinergic Zimelidine dihydrochloride −0.6490088 0.2581663 Serotonin Tyrphostin 1 −0.6423812 0.2603129 Phosphorylation N,N,N′,N′-Tetramethylazodicarboxamide −0.6392844 0.261319 Cell Stress Isotharine mesylate −0.6391695 0.2613563 Adrenoceptor 1-(2-Methoxyphenyl)piperazine hydrochloride −0.638803 0.2614756 Serotonin ET-18-OCH3 −0.6258823 0.2656961 Lipid Enoximone −0.6236691 0.2664225 Cyclic Nucleotides NAN-190 hydrobromide −0.6185897 0.2680934 Serotonin L-655,708 −0.6131906 0.2698752 Benzodiazepine Oxiracetam −0.6130565 0.2699195 Nootropic Ethosuximide −0.6123992 0.2701368 Anticonvulsant Cortexolone −0.6087203 0.2713549 Hormone Naloxonazine dihydrochloride −0.6060679 0.2722348 Opioid N-(4-Amino-2-chlorophenyl)phthalimide −0.602074 0.2735624 Anticonvulsant Cysteamine hydrochloride −0.5988785 0.274627 Somatostatin Vanillic acid diethylamide −0.5948053 0.2759868 Vanilloid ODQ −0.5921983 0.2768589 Cyclic Nucleotides L-Glutamic acid, N-phthaloyl- −0.5891419 0.277883 Glutamate L-Leucinethiol, oxidized dihydrochloride −0.5840121 0.2796061 Biochemistry 3,4-Dihydroxyphenylacetic acid −0.5831905 0.2798825 Dopamine MK-912 −0.582011 0.2802796 Adrenoceptor Cortisone −0.5806734 0.2807303 Hormone 17alpha-hydroxyprogesterone −0.5782524 0.2815469 Hormone Cantharidin −0.5781481 0.2815821 Phosphorylation Fenspiride hydrochloride −0.576236 0.2822278 Adrenoceptor 2-Cyelooctyl-2-hydroxyethylamine hydrochloride −0.5746572 0.2827616 Neurotransmission (B1)-Isoproterenol hydrochloride −0.571712 0.2837586 Adrenoceptor 4-Hydroxy-3-methoxyphenylacetic acid −0.5672969 0.2852562 Dopamine 3-Nitropropionic acid −0.5631368 0.2866709 Cell Stress beta-Estradiol −0.5622806 0.2869624 Hormone Etodolac −0.5581734 0.288363 Prostaglandin Doxycycline hydrochloride −0.5578035 0.2884893 Antibiotic MHPG sulfate potassium −0.5556352 0.2892301 Adrenoceptor Cantharidic Acid −0.5529217 0.2901585 Phosphorylation (S)-MAP4 hydrochloride −0.5525297 0.2902927 Glutamate Linopirdine −0.5525235 0.2902949 Cholinergic Pireuzepine dihydrochloride −0.5449552 0.2928922 Cholinergic 1-(4-Fluorobenzyl)-5-methoxy-2-methylindole-3-acetic acid −0.5376019 0.2954259 Multi-Drug Resistance (S)-Propranolol hydrochloride −0.5346361 0.2964508 Adrenoceptor (−)-Epinephrine bitartrate −0.5304149 0.2979122 Adrenoceptor 3,5-Dinitrocatechol −0.5293574 0.2982788 Neurotransmission Imipramine hydrochloride −0.527183 0.2990333 Serotonin Spironolactone −0.5258429 0.2994987 Hormone DL-threo-beta-hydroxyaspartic acid −0.5215278 0.3009996 Glutamate Spiperone hydrochloride −0.5167586 0.3026623 Dopamine GW2974 −0.5163796 0.3027947 Phosphorylation (−)-Cotinine −0.509877 0.3050688 Cholinergic Phosphoramidon disodium −0.5097313 0.3051198 Biochemistry L-703,606 oxalate −0.5068733 0.3061218 Tachykinin R-(−)-Desmethyldeprenyl hydrochloride −0.5056059 0.3065667 Neurotransmission 2,6-Difluoro-4-[2-(phenylsulfonylamino)ethylthio]phenoxyacetamide −0.4982651 0.3091486 Glutamate Loperamide hydrochloride −0.4975951 0.3093847 Opioid WAY-100635 maleate −0.4965254 0.3097619 Serotonin Salmeterol −0.4895786 0.312216 Adrenoceptor Ofloxacin −0.4888508 0.3124737 Antibiotic NS-1619 −0.4877995 0.3128459 K+ Channel 3-Hydroxybenzylhydrazine dihydrochloride −0.4866413 0.3132563 Biochemistry Flupirtine maleate −0.4839672 0.3142046 Glutamate Emodin −0.4834599 0.3143846 Phosphorylation Acetylsalicylic acid −0.4811745 0.3151962 Prostaglandin (+)-trans-(1R,2R)-U-50488 hydrochloride −0.4732357 0.3180225 Opioid L-Glutamic acid hydrochloride −0.4726761 0.3182221 Glutamate Tetrahydrozoline hydrochloride −0.4692774 0.3194357 Adrenoceptor Genistein −0.4689112 0.3195666 Phosphorylation PK 11195 −0.4675507 0.320053 GABA NO-711 hydrochloride −0.4617631 0.3221256 GABA Felbamate −0.4585863 0.3232656 Glutamate Diethylenetriaminepentaacetic acid −0.4575677 0.3236315 Biochemistry SNC80 −0.4574846 0.3236614 Opioid Isonipecotic acid −0.4569003 0.3238714 GABA (B1)-Quinpirole dihydrochloride −0.4512555 0.3259027 Dopamine (−)-Scopolamine methyl nitrate −0.4508293 0.3260563 Cholinergic (B1)-p-Aminoglutethimide −0.444087 0.3284898 Biochemistry Alloxazine −0.4424311 0.3290886 Adenosine GABA −0.4389397 0.3303526 GABA CV-3988 −0.4370903 0.3310229 Cytokines & Growth Factors (B1)-AMPA hydrobromide −0.4272214 0.334609 Glutamate S-(4-Nitrobenzyl)-6-thioinosine −0.4271344 0.3346407 Adenosine DL-alpha-Difluoromethylornithine hydrochloride −0.4243649 0.3356498 Angiogenesis Piperidine-4-sulphonic acid −0.4237939 0.3358581 GABA S(−)-3PPP hydrochloride −0.4205348 0.3370474 Dopamine Ammonium pyrrolidinedithiocarbamate −0.4167557 0.3384286 Nitric Oxide Dihydrexidine hydrochloride −0.4153013 0.3389607 Dopamine N-(p-Isothiocyanatophenethyl)spiperone hydrochloride −0.4152099 0.3389941 Dopamine Amperozide hydrochloride −0.4126439 0.3399338 Serotonin N-Oleoylethanolamine −0.4116341 0.3403038 Sphingolipid CGP-7930 −0.411034 0.3405238 GABA Tyrphostin AG 126 −0.4102296 0.3408188 Phosphorylation LY-367,265 −0.4069604 0.3420185 Serotonin Triprolidine hydrochloride −0.4060897 0.3423383 Histamine BW 284c51 −0.4016895 0.3439563 Cholinergic 7-Chloro-4-hydroxy-2-phenyl-1,8-naphthyridine −0.4009727 0.3442201 Adenosine Indirubin-3′-oxime −0.3965032 0.3458669 Phosphorylation 2-Chloroadenosine −0.3960315 0.3460409 Adenosine Tyrphostin AG 538 −0.3954838 0.346243 Phosphorylation 5alpha-Androstane-3alpha, 17beta-diol −0.3811247 0.3515553 Hormone L-N6-(1-Iminoethyl)lysine hydrochloride −0.3808868 0.3516436 Nitric Oxide Piracetam −0.375802 0.353532 Glutamate Flumazenil −0.3664171 0.3570269 Benzodiazepine ICI 204,448 hydrochloride −0.3635568 0.3580945 Opioid Maprotiline hydrochloride −0.3614509 0.3588812 Adrenoceptor Naltriben methanesulfonate −0.3605906 0.3592028 Opioid Glibenclamide −0.3600391 0.359409 K+ Channel Ro 41-0960 −0.3600208 0.3594158 Neurotransmission Indomethacin −0.3562981 0.3608087 Prostaglandin S-5-Iodowillardiine −0.3551315 0.3612455 Glutamate Bromoacetylcholine bromide −0.3547425 0.3613913 Cholinergic IIK7 −0.3544091 0.3615162 Melatonin trans-Azetidine-2,4-dicarboxylic acid −0.3491146 0.3635016 Glutamate Levallorphan tartrate −0.3464543 0.3645007 Opioid Oleic Acid −0.3449339 0.365072 Phosphorylation 3-Tropanylindole-3-carboxylate methiodide −0.3436416 0.3655579 Serotonin Zardaverine −0.3412328 0.3664641 Cyclic Nucleotides 8-Methoxymethyl-3-isobutyl-1-methylxanthine −0.3402529 0.366833 Cyclic Nucleotides LY-53,857 maleate −0.3381844 0.3676121 Serotonin Acetyl-beta-methylcholine chloride −0.3381749 0.3676157 Cholinergic (S)-3,5-Dihydroxyphenylglycine −0.3364181 0.3682778 Glutamate Benazoline oxalate −0.3347687 0.3688998 Imidazoline Adenosine amine congener −0.3344655 0.3690142 Adenosine Piribedil maleate −0.3344511 0.3690196 Dopamine Centrophenoxine hydrochloride −0.3302342 0.3706115 Nootropic Arcaine sulfate −0.3298798 0.3707454 Glutamate (B1)-Epinephrine hydrochloride −0.3279434 0.3714772 Adrenoceptor Quipazine, N-methyl-, dimaleate −0.3254481 0.372421 Serotonin Tetradecylthioacetic acid −0.3237663 0.3730575 Transcription Phentolamine mesylate −0.3190977 0.3748262 Adrenoceptor Kainic acid −0.3168627 0.3756739 Glutamate Tracazolate −0.3151455 0.3763256 GABA Nalidixic acid sodium −0.3144509 0.3765893 Antibiotic Naltrindole hydrochloride −0.3140306 0.3767489 Opioid DL-Thiorphan −0.3115796 0.37768 Neurotransmission Ipratropium bromide −0.3080062 0.3790388 Cholinergic Debrisoquin sulfate −0.3034256 0.3807828 Neurotransmission Tolbutamide −0.3031914 0.380872 Hormone U-62066 −0.3026318 0.3810852 Opioid Papaverine hydrochloride −0.2991801 0.3824013 Cyclic Nucleotides DL-Cycloserine −0.2985721 0.3826333 Sphingolipid (−)-trans-(1S,2S)-U-50488 hydrochloride −0.2970526 0.3832132 Opioid S(+)-Isoproterenol (+)-bitartrate −0.2963012 0.3835 Adrenoceptor Nifedipine −0.2937469 0.3844757 Ca2+ Channel 5-(N-Ethyl-N-isopropyl)amiloride −0.2885522 0.386462 Ion Pump P1,P4-Di(adenosine-5′)tetraphosphate triammonium −0.2866674 0.3871835 Biochemistry JL-18 −0.2861311 0.3873888 Dopamine (B1)-Sulpiride −0.2841113 0.3881626 Dopamine Pargyline hydrochloride −0.2793742 0.3899788 Neurotransmission 1400W dihydrochloride −0.2748955 0.3916983 Nitric Oxide (B1)-Metoprolol (+)-tartrate −0.2688977 0.3940042 Adrenoceptor Quinine sulfate −0.2685721 0.3941295 K+ Channel MRS 2159 −0.2666194 0.3948811 P2 Receptor Phorbol 12-myristate 13-acetate −0.2649849 0.3955105 Phosphorylation 4-Imidazoleacrylic acid −0.2635155 0.3960766 Histamine (B1)-Ibuprofen −0.2623381 0.3965304 Prostaglandin Tyrphostin 25 −0.2591217 0.3977707 Phosphorylation Ropinirole hydrochloride −0.2551545 0.3993019 Dopamine Ebselen −0.2514811 0.4007211 Leukotriene Iproniazid phosphate −0.2492467 0.401585 Neurotransmission (B1)-p-Chlorophenylalanine −0.2471057 0.4024132 Neurotransmission Etazolate hydrochloride −0.2465468 0.4026295 Adenosine Imetit dihydrobromide −0.245242 0.4031345 Histamine Melatonin −0.2407208 0.4048858 Melatonin SKF 89976A hydrochloride −0.2327776 0.4079671 GABA Pimozide −0.2323351 0.4081389 Dopamine Resveratrol −0.2295098 0.4092364 Prostaglandin (−)-Physostigmine −0.2178478 0.4137739 Cholinergic Phenytoin sodium −0.2165555 0.4142774 Anticonvulsant Metrifudil −0.2122911 0.41594 Adenosine Hydrochlorothiazide −0.2120003 0.4160534 Biochemistry S-Methylisothiourea hemisulfate −0.211117 0.416398 Nitric Oxide UK 14,304 −0.2102812 0.4167241 Adrenoceptor Adenosine −0.2085555 0.4173976 Adenosine Pheniramine maleate −0.2062238 0.4183081 Histamine Hydroxytacrine maleate −0.2043258 0.4190494 Cholinergic Guanidinyl-naltrindole di-trifluoroacetate −0.2037007 0.4192937 Opioid (+)-Bicuculline −0.1988579 0.4211869 GABA GR 125487 sulfamate salt −0.1942361 0.4229955 Serotonin Sulindac −0.1941855 0.4230153 Prostaglandin Chlorpropamide −0.1900506 0.4246347 Hormone H-9 dihydrochloride −0.1898999 0.4246938 Phosphorylation Nocodazole −0.1890617 0.4250222 Cytoskeleton and ECM Ciclosporin −0.1858442 0.4262835 Phosphorylation Clodronic acid −0.1841811 0.4269357 Cytoskeleton and ECM Triamcinolone −0.1839952 0.4270086 Hormone Alaproclate hydrochloride −0.172486 0.4315277 Serotonin U-75302 −0.1722133 0.4316349 Leukotriene O-Methylserotonin hydrochloride −0.1719634 0.4317331 Serotonin ARL 67156 trisodium salt −0.1680119 0.433287 P2 Receptor GW5074 −0.1618707 0.4357038 Phosphorylation p-Iodoclonidine hydrochloride −0.1606282 0.4361931 Adrenoceptor 1-[2-(Trifluoromethyl)phenyl]imidazole −0.1576174 0.4373791 Nitric Oxide L-Cycloserine −0.1551811 0.4383393 Sphingolipid Thioperamide maleate −0.1536629 0.4389378 Histamine (B1)-Synephrine −0.1488224 0.4408469 Adrenoceptor Tyrphostin AG 528 −0.148142 0.4411154 Phosphorylation Thiocitrulline −0.1474445 0.4413906 Nitric Oxide S-(−)-Lisuride −0.1473193 0.44144 Dopamine D-Serine −0.142851 0.4432039 Glutamate SKF 75670 hydrobromide −0.1421094 0.4434968 Dopamine Fusaric acid −0.1412847 0.4438225 Dopamine Memantine hydrochloride −0.1410286 0.4439237 Glutamate 2-Iodomelatonin −0.1348453 0.4463671 Melatonin Citicoline sodium −0.1331469 0.4470386 Lipid R-(−)-Fluoxetine hydrochloride −0.1280696 0.449047 Serotonin Y-27632 dihydrochloride −0.1254747 0.4500739 Phosphorylation 8-Cyclopentyl-1,3-dimethylxanthine −0.1247866 0.4503462 Adenosine Xamoterol hemifumarate −0.1243226 0.4505299 Adrenoceptor L-655,240 −0.1210308 0.4518333 Thromboxane Naftopidil dihydrochloride −0.1172241 0.4533412 Adrenoceptor S(−)-IBZM −0.1165784 0.4535971 Dopamine Flutamide −0.1132999 0.4548964 Hormone Lidocaine hydrochloride −0.1110713 0.4557799 Na+ Channel (B1)-Chloro-APB hydrobromide −0.1110031 0.4558069 Dopamine Arecoline hydrobromide −0.1109986 0.4558087 Cholinergic S(−)-DS 121 hydrochloride −0.0997976 0.4602525 Dopamine (+)-MK-801 hydrogen maleate −0.0980507 0.460946 Glutamate Foliosidine −0.0968991 0.4614033 Anticonvulsant Valproic acid sodium −0.0949317 0.4621846 Anticonvulsant McN-A-343 −0.0889691 0.4645532 Cholinergic 1,3-Dipropyl-7-methylxanthine −0.0889564 0.4645583 Adenosine Pindolol −0.0789539 0.4685346 Adrenoceptor DL-erythro-Dihydrosphingosine −0.0785022 0.4687143 Phosphorylation Ruthenium red −0.0738764 0.4705544 Ion Pump Disopyramide phosphate −0.0718701 0.4713527 K+ Channel 8-Cyclopentyl-1,3-dipropylxanthine −0.0702081 0.472014 Adenosine Betaine aldehyde chloride −0.0700722 0.4720681 Cholinergic Demeclocycline hydrochloride −0.0645223 0.4742772 Antibiotic Vancomycin hydrochloride from Streptomyces orientalis −0.0635226 0.4746752 Antibiotic Terazosin hydrochloride −0.0572176 0.4771859 Adrenoceptor 3-Iodo-L-tyrosine −0.0484383 0.4806835 Neurotransmission p-Aminoclonidine hydrochloride −0.0477571 0.4809549 Adrenoceptor gamma-D-Glutamylaminomethylsulfonic acid −0.0464941 0.4814582 Glutamate SKF 89626 −0.0436857 0.4825775 Dopamine Hydrocortisone 21-hemisuccinate sodium −0.0403285 0.4839156 Hormone Carbachol −0.0338084 0.486515 Cholinergie Lansoprazole −0.0336022 0.4865972 Ion Pump 4-Chloromercuribenzoic acid −0.031935 0.4872619 Biochemistry Nialamide −0.0293668 0.488286 Neurotransmission N-Ethylmaleimide −0.0281638 0.4887658 Biochemistry Mibefradil dihydrochloride −0.026925 0.4892598 Ca2+ Channel Methysergide maleate −0.0198344 0.4920877 Serotonin Tetracaine hydrochloride −0.0195299 0.4922092 Na+ Channel 3-(1H-Imidazol-4-yl)propyl di(p-fluorophenyl)methyl ether −0.0146618 0.494151 Histamine hydrochloride Phenylbenzene-omega-phosphono-alpha-amino acid −0.0142281 0.494324 Glycine R(+)-IAA-94 −0.0101507 0.4959505 Cl− Channel 1,4-Dideoxy-1,4-imino-D-arabinitol −0.0086167 0.4965625 Phosphorylation 5-Fluoroindole-2-carboxylic acid −0.0075488 0.4969885 Glutamate MRS 1845 −0.0061956 0.4975283 Ca2+ Channel S-(p-Azidophenacyl)glutathione −0.0027604 0.4988988 Multi-Drug Resistance Bretylium tosylate −0.0017093 0.4993181 Adrenoceptor MRS 1523 −0.0013116 0.4994768 Adenosine Aminoguanidine hydrochloride −0.000731 0.4997084 Nitric Oxide Xanthine amine congener 0.0011645 0.4995354 Adenosine Roscovitine 0.0027304 0.4989107 Phosphorylation Acetyithiocholine chloride 0.0042231 0.4983152 Cholinergic Na-p-Tosyl-L-lysine chloromethyl ketone hydrochloride 0.0048117 0.4980804 Cyclic Nucleotides Benserazide hydrochloride 0.0074665 0.4970213 Biochemistry 6-Nitroso-1,2-beazopyrone 0.0113164 0.4954855 Transcription GW1929 0.0150842 0.4939825 Transcription Ranitidine hydrochloride 0.0227452 0.4909267 Histamine 1,5-Isoquinolinediol 0.0267361 0.4893351 Apoptosis (+)-Bromocriptine methanesulfonate 0.0279151 0.4888649 Dopamine R(+)-Butylindazone 0.0292353 0.4883385 Ion Pump 5-Hydroxy-L-tryptophan 0.0301111 0.4879892 Serotonin SB 228357 0.0342571 0.4863361 Serotonin DPMA 0.0362806 0.4855293 Adenosine 5-(N,N-hexamethylene)amiloride 0.0385541 0.484623 Ion Pump Estrone 0.0408124 0.4837227 Hormone YS-035 hydrochloride 0.0431073 0.482808 Ca2+ Channel (−)-Nicotine hydrogen tartrate salt 0.0449771 0.4820628 Cholinergic Diazoxide 0.0451082 0.4820105 K+ Channel LY-310,762 hydrochloride 0.0511143 0.4796172 Serotonin Fenoldopam bromide 0.0521932 0.4791874 Dopamine MHPG piperazine 0.052756 0.4789632 Adrenoceptor Famotidine 0.0548884 0.4781137 Histamine Milrinone 0.0550597 0.4780455 Cyclic Nucleotides Methyl beta-carboline-3-carboxylate 0.0602298 0.4759863 Benzodiazepine Oxaprozin 0.066155 0.4736272 Prostaglandin Nalbuphine hydrochloride 0.07032 0.4719695 Opioid Cyclobenzaprine hydrochloride 0.0718594 0.4713569 Serotonin T-0156 0.0770873 0.4692771 Cyclic Nucleotides Chlorambucil 0.0807801 0.4678084 DNA L-Methionine sulfoximine 0.0867138 0.4654495 Glutamate PD 404,182 0.0905517 0.4639244 Biochemistry 3-Methyl-6-(3-[trifluoromethyl]phenyl)-1,2,4-triazolo[4,3- 0.0909474 0.4637672 Benzodiazepine b]pyridazine 6-Methyl-2-(phenylethynyl)pyridine hydrochloride 0.0936604 0.4626895 Glutamate (B1)-Norepinephrine (+)bitartrate 0.0990286 0.4605578 Adrenoceptor GR 4661 0.1015268 0.4595661 Serotonin S-(4-Nitrobenzyl)-6-thioguanosine 0.1016687 0.4595098 Adenosine Azelaic acid 0.1056824 0.4579172 DNA Metabolism Metrazoline oxalate 0.107342 0.4572588 Imidazoline Nilutamide 0.1188464 0.4526985 Hormone Spiroxatrine 0.1219344 0.4514755 Serotonin Desipramine hydrochloride 0.1226472 0.4511932 Adrenoceptor Tetraethylammonium chloride 0.1229511 0.4510729 Cholinergic 6,7-Dichloroquinoxaline-2,3-dione 0.1273921 0.449315 Glutamate DL-p-Chlorophenylalanine methyl ester hydrochloride 0.1276252 0.4492228 Neurotransmission Fluvoxamine maleate 0.1322979 0.4473743 Serotonin NBI 27914 0.134476 0.4465131 Neurotransmission Lomefloxacin hydrochloride 0.1373887 0.4453618 Antibiotic NG-Nitro-L-arginine 0.1385058 0.4449203 Nitric Oxide 1,10-Diaminodecane 0.1393232 0.4445974 Glutamate Allopurinol 0.1473025 0.4414466 Cell Stress AIDA 0.1540169 0.4387982 Glutamate (B1)-cis-Piperidine-2,3-dicarboxylic acid 0.1553074 0.4382895 Glutamate Propentofylline 0.1562987 0.4378988 Adenosine Urapidil hydrochloride 0.157212 0.4375389 Adrenoceptor L-Aspartic acid 0.1631695 0.4351925 Glutamate Pentolinium di[L(+)-tartrate] 0.1661577 0.4340164 Cholinergic Tomoxetine 0.1672426 0.4335896 Adrenoceptor (−)-cis-(1S,2R)-U-50488 tartrate 0.1710795 0.4320806 Neurotransmission Tranilast 0.173632 0.4310773 Leukotriene Cilostamide 0.1756328 0.4302912 Cyclic Nucleotides Tyrphostin 47 0.1775006 0.4295576 Phosphorylation CGS-15943 0.1783497 0.4292242 Adenosine Muscimol hydrobromide 0.1862631 0.4261192 GABA 4-Androsten-4-ol-3,17-dione 0.1944016 0.4229307 Hormone Palmitoyl-DL-Carnitine chloride 0.199541 0.4209198 Phosphorylation Fiduxosin hydrochloride 0.2004519 0.4205636 Adrenoceptor Dihydroouabain 0.2033806 0.4194188 Ion Pump Quazinone 0.2046132 0.4189372 Cyclic Nucleotides (S)-ENBA 0.2078462 0.4176745 Adenosine Moxonidine hydrochloride 0.2170959 0.4140668 Adrenoceptor L-Tryptophan 0.2240902 0.4113435 Serotonin Pirenperone 0.2278841 0.4098682 Serotonin 1-(1-Naphthyl)piperazine hydrochloride 0.2300827 0.4090137 Serotonin Pyridostigmine bromide 0.2310856 0.4086241 Cholinergic 5-hydroxydecanoic acid sodium 0.2331661 0.4078162 K+ Channel Isoxanthopterin 0.2339176 0.4075245 Cell Stress Thioridazine hydrochloride 0.2356029 0.4068704 Dopamine (−)-Isoproterenol hydrochloride 0.2366585 0.4064609 Adrenoceptor Dilazep hydrochloride 0.2448304 0.4032939 Adenosine SKF 94836 0.245798 0.4029193 Calcium Signaling Bromoenol lactone 0.2484302 0.4019008 Lipid RX 821002 hydrochloride 0.2490354 0.4016667 Adrenoceptor Phthalamoyl-L-glutamic acid trisodium 0.2508627 0.4009601 Glutamate Piroxicam 0.2527019 0.4002493 Prostaglandin (B1)-Pindobind 0.257465 0.3984099 Adrenoceprors Hydralazine hydrochloride 0.2592444 0.3977233 Neurotransmission p-MPPI hydrochloride 0.2605884 0.397205 Serotonin Benoxathian hydrochloride 0.2652651 0.3954026 Adrenoceptor Lidocaine N-ethyl bromide quaternary salt 0.265314 0.3953838 Na+ Channel Beclomethasone 0.2669712 0.3947457 Hormone Bupropion hydrochloride 0.267118 0.3946891 Dopamine SU 4312 0.2691773 0.3938966 Phosphorylation Hypotaurine 0.2752082 0.3915782 Cell Stress L-3,4-Dihydroxyphenylalanine methyl ester hydrochloride 0.2768938 0.3909308 Dopamine ATPA 0.2831538 0.3885295 Glutamate L-368,899 0.2909288 0.3855529 Neurotransmission Xylometazoline hydrochloride 0.2960167 0.3836087 Adrenoceptor Diclofenac sodium 0.2987801 0.3825539 Prostaglandin NADPH tetrasodium 0.3021176 0.3812812 Nitric Oxide Rottlerin 0.3042416 0.3804719 Phosphorylation L-165,041 0.3061865 0.3797313 Lipid Signaling 1-Methylbistamine dihydrochloride 0.3067951 0.3794997 Histamine BRL 15572 0.311685 0.37764 Serotonin trans-(B1)-ACPD 0.3149054 0.3764167 Glutamate HA-1004 hydrochloride 0.3161003 0.3759632 Phosphorylation SU 6656 0.3164605 0.3758265 Phosphorylation Dobutamine hydrochloride 0.318514 0.3750475 Adrenoceptor Caffeic Acid 0.3199066 0.3745196 Cell Stress (B1)-CPP 0.3213292 0.3739805 Glutamate MDL 26,630 trihydrochloride 0.3273648 0.371696 Glutamate 4-DAMP methiodide 0.3311398 0.3702694 Cholinergic Sandoz 58-035 0.3324572 0.369772 Lipid Tyrphostin AG 112 0.3332617 0.3694684 Phosphorylation 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride 0.3351856 0.3687425 Phosphorylation N-p-Tosyl-L-phenylalanine chloromethyl ketone 0.3366567 0.3681879 Biochemistry BRL 54443 maleate 0.3378207 0.3677491 Serotonin (B1)-alpha-Lipoic Acid 0.3418414 0.3662351 Cell Stress Ro 04-6790 dihydrochloride 0.3427992 0.3658748 Serotonin (B1)-Propranolol hydrochloride 0.3567231 0.3606496 Adrenoceptor 6,7-ADTN hydrobromide 0.3569595 0.3605611 Dopamine Amifostine 0.3591546 0.3597397 Cell Stress SCH-202676 hydrobromide 0.3598564 0.3594773 G protein THIP hydrochloride 0.3613052 0.3589356 GABA A-315456 0.3628354 0.3583639 Adrenoceptor 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride 0.3634327 0.3581408 Biochemistry Furegrelate sodium 0.3638005 0.3580035 Phosphorylation Thio-NADP sodium 0.3660898 0.357149 Intracellular Calcium Theophylline 0.3698936 0.3557309 Adenosine alpha-Methyl-DL-tyrosine methyl ester hydrochloride 0.3702682 0.3555913 Neurotransmission Xylazine hydrochloride 0.3754966 0.3536456 Adrenoceptor 6-Hydroxymelatonin 0.376743 0.3531823 Melatonin Propofol 0.3768262 0.3531514 Cholinergic 5-fluoro-5′-deoxyuridine 0.3786747 0.3524647 DNA Metabolism Ibudilast 0.3787299 0.3524442 Cyclic Nucleotides Telenzepine dihydrochloride 0.3813181 0.3514836 Cholinergic N-(2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl)-3-methoxybenzamide 0.3828304 0.3509228 Dopamine N-arachidonylglycine 0.3870739 0.3493507 Cannabinoid nor-Binaltorphimine dihydrochloride 0.3880758 0.34898 Opioid Naltrexone hydrochloride 0.3891105 0.3485972 Opioid Spermine tetrahydrochloride 0.3941956 0.3467183 Glutamate Flunarizine dihydrochloride 0.3954139 0.3462687 Ion Pump BU224 hydrochloride 0.404453 0.3429398 Imidazoline Pancuronium bromide 0.407652 0.3417646 Cholinergic Ergocristine 0.4077764 0.3417189 Dopamine Wortmannin from Penicillium funiculosum 0.4078684 0.3416852 Phosphorylation Caffeine 0.4113488 0.3404084 Adenosine Se-(methyl)selenocysteine hydrochloride 0.4115883 0.3403206 Cell Cycle Cirazoline hydrochloride 0.4239458 0.3358027 Adrenoceptor SKY 95282 dimaleate 0.4240619 0.3357603 Histamine Progesterone 0.4251895 0.3353493 Hormone Hydroquinone 0.4279698 0.3343366 Leukotriene Vinpocetine 0.4328502 0.3325618 Cyclic Nucleotides YC-1 0.4334912 0.332329 Cyclic Nucleotides Lonidamine 0.4358327 0.331479 Cell Stress (+)-Quisqualic acid 0.436121 0.3313745 Glutamate Minocycline hydrochloride 0.4418815 0.3292875 Cell Cycle 3-alpha,21-Dihydroxy-5-alpha-pregnan-20-one 0.4440753 0.3284941 GABA L-701,324 0.4512614 0.3259006 Glutamate Orphenadrine hydrochloride 0.4547976 0.3246274 Cholinergic Imazodan 0.4616369 0.3221709 Cyclic Nucleotides N-Oleoyldopamine 0.4632861 0.3215796 Neurotransmission N-Acetyldopamine monohydrate 0.4667428 0.320342 Dopamine Promethazine hydrochloride 0.4745838 0.3175418 Histamine 1-(5-Isoquinolinylsulfonyl)-3-methylpiperazine dihydrochloride 0.4769032 0.3167155 Phosphorylation Antozoline hydrochloride 0.4853666 0.3137082 Imidazoline Amfonelic acid 0.4880186 0.3127683 Dopamine 9-cyclopentyladenine 0.4988192 0.3089534 Cyclic Nucleotides Chloroquine diphosphate 0.4992524 0.3088008 DNA L-732,138 0.5027332 0.3075759 Tachykinin (+)-Catechin Hydrate 0.5105437 0.3048353 Cell Stress L-Buthionine-sulfoximine 0.5134301 0.3038252 Multi-Drug Resistance (B1)-Thalidomide 0.5210337 0.3011717 Cytoskeleton and ECM 1-Aminobenzotriazole 0.5235927 0.3002809 Multi-Drug Resistance Rilmenidine hemifumarate 0.5264123 0.2993009 Imidazoline N6-2-Phenylethyladenosine 0.5312319 0.2976291 Adenosine Taurine 0.5327512 0.2971029 Glycine Diltiazem hydrochloride 0.5395341 0.2947592 Ca2+ Channel CR 2945 0.5450668 0.2928538 Cholecystokinin O-Phospho-L-serine 0.5471921 0.2921234 Glutamate Clozapine 0.5473261 0.2920774 Dopamine Beuzamide 0.5498247 0.2912198 Apoptosis alpha-Lobeline hydrochloride 0.5498547 0.2912095 Cholinergic Procaine hydrochloride 0.5501378 0.2911124 Na+ Channel L-Arginine 0.5591786 0.2880199 Nitric Oxide SQ 22536 0.5615523 0.2872105 Cyclic Nucleotides K 185 0.5674427 0.2852067 Melatonin Trimipramine maleate 0.5676856 0.2851242 Serotonin Aurintricarboxylic acid 0.5709183 0.2840275 Apoptosis 2-Methyl-5-hydroxytryptamine maleate 0.5718311 0.2837182 Serotonin 2-Phenylaminoadenosine 0.5727729 0.2833992 Adenosine VUF 5574 0.5811367 0.2805742 Adenosine Me-3,4-dephostatin 0.5834297 0.279802 Phosphorylation Ketoconazole 0.5860476 0.2789218 Multi-Drug Resistance Ro 20-1724 0.587371 0.2784773 Cyclic Nucleotides Agmatine sulfate 0.5880971 0.2782336 Imidazoline Sulindac sulfone 0.5923798 0.2767982 Prostaglandin Oxatomide 0.5957331 0.2756768 Immune System Piceatannol 0.5957518 0.2756705 Phosphorylation (−)-3-Methoxynaltrexone hydrochloride 0.5963498 0.2754708 Opioid (−)-Naproxen sodium 0.6024196 0.2734474 Prostaglandin (+)-Cyclazocine 0.6116099 0.2703979 Opioid S(−)-Atenolol 0.6170341 0.2686061 Adrenoceptor Primidone 0.6186602 0.2680701 Anticonvulsant Dephostatin 0.6209485 0.2673167 Phosphorylation CL 316, 243 0.6212351 0.2672225 Adrenoceptor Cephapirin sodium 0.6219276 0.2669947 Antibiotic JWH-015 0.6222735 0.266881 Cannabinoid Methapyrilene hydrochloride 0.6275722 0.2651421 Histamine (−)-Eseroline fumarate 0.6338836 0.2630784 Cholinergic DL-Stearoylcarnitine chloride 0.6377652 0.2618133 Phosphorylation Terbutaline hemisulfate 0.6409003 0.2607937 Adrenoceptor Bestatin hydrochloride 0.6432311 0.2600371 Biochemistry Droperidol 0.6446544 0.2595756 Dopamine (−)-Scopolamine,n-Butyl-, bromide 0.6485586 0.2583119 Cholinergic CGP 20712A methanesulfonate 0.6490545 0.2581516 Adrenoceptor Procainamide hydrochloride 0.6535257 0.2567087 Na+ Channel N-omega-Methyl-5-hydroxytryptamine oxalate salt 0.6559542 0.2559268 Serotonin (B1)-8-Hydroxy-DPAT hydrobromide 0.6561179 0.2558741 Serotonin Nomifensine maleate 0.6692709 0.2516614 Dopamine 6(5H)-Phenanthridinone 0.6765123 0.2493577 Transcription H-7 dihydrochloride 0.6812631 0.2478525 Phosphorylation IEM-1460 0.6847965 0.2467362 Glutamate Rutaecarpine 0.6856989 0.2464515 K+ Channel Tiapride hydrochloride 0.6889364 0.2454316 Dopamine S-Nitrosoglutathione 0.6977851 0.2426558 Nitric Oxide N-Methyl-beta-carboline-3-carboxamide 0.6987585 0.2423515 GABA Kynurenic acid 0.7018101 0.2413988 Glutamate AGN 192403 hydrochloride 0.7031502 0.2409811 Imidazoline Amitriptyline hydrochloride 0.7066229 0.2399004 Adrenoceptor Uridine 5′-diphosphate sodium 0.7073999 0.239659 P2 Receptor Oxybutynin Chloride 0.7079682 0.2394825 Cholinergic U0126 0.7109655 0.2385528 Phosphorylation Cephradine 0.7111821 0.2384857 Antibiotic N-Succinyl-L-proline 0.7245654 0.2343593 Neurotransmission BW 723C86 0.7247268 0.2343098 Serotonin Chelidamic acid 0.7260765 0.2338959 Glutamate (B1)-alpha-Methyl-4-carboxyphenylglycine 0.726971 0.2336219 Glutamate N6-Phenyladenosine 0.7283359 0.233204 Adenosine N6-Methyladenosine 0.7424208 0.2289162 Adenosine DL-Homatropine hydrobromide 0.7439854 0.2284426 Cholinergic Sodium Oxamate 0.744881 0.2281718 Biochemistry ZM 39923 hydrochloride 0.7456711 0.2279331 Phosphorylation Chlorpromazine hydrochloride 0.7505935 0.2264487 Dopamine 1,3-Dimethyl-8-phenylxanthine 0.7517894 0.2260889 Adenosine Terfenadine 0.7552995 0.2250346 Histamine Protriptyline hydrochloride 0.7602722 0.223546 Adrenoceptor AB-MECA 0.7603821 0.2235131 Adenosine 1-(4-Hydroxybenzyl)imidazole-2-thiol 0.7627544 0.2228049 Dopamine 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole 0.7716697 0.2201551 Hormone 2,4-Dinitrophenyl 2-fluoro-2-deoxy-beta-D-glucopyranoside 0.7720141 0.220053 Biochemistry Picrotoxin 0.7771163 0.2185451 GABA FSCPX 0.782467 0.2169701 Adenosine Hemicholinium-3 0.7870667 0.2156214 Cholinergic SKY 83565 hydrobromide 0.7894819 0.2149152 Dopamine Phenylbutazone 0.790229 0.214697 Prostaglandin L-162,313 0.7922885 0.2140962 Neurotransmission SB 205384 0.7968442 0.2127708 GABA Dantrolene sodium 0.7984689 0.2122992 Intracellular Calcium DCEBIO 0.8098904 0.2090016 K+ Channel Paromomycin sulfate 0.8210123 0.2058196 Antibiotic Cilostazol 0.8218663 0.2055765 Cyclic Nucleotides Tropicamide 0.8227286 0.2053312 Cholinergic L-Glutamine 0.8277987 0.2038923 Glutamate Nisoxetine hydrochloride 0.8335605 0.2022643 Adrenoceptor BTCP hydrochloride 0.8361494 0.2015354 Dopamine Diphenhydramine hydrochloride 0.8449488 0.1990697 Histamine (B1)-Bay K 8644 0.8527083 0.1969106 Ca2+ Channel Oxotremorine sesquifumarate salt 0.8551621 0.1962307 Cholinergic Chloroethylclonidine dihydrochloride 0.8606017 0.1947287 Adrenoceptor 4-Diphenylacetoxy-N-(2-chloroethyl)piperidine hydrochloride 0.86449 0.1936594 Cholinergic TPMPA 0.874196 0.1910058 GABA Betamethasone 0.8811058 0.1891303 Hormone SKF 86466 0.8822325 0.1888255 Adrenoceptor Gabapentin 0.883778 0.188408 Anticonvulsant Hispidin 0.8895833 0.1868448 Phosphorylation 5,7-Dichlorokynurenic acid 0.9010634 0.1837773 Glutamate PD 98,059 0.9027126 0.1833392 Phosphorylation Farnesylthiosalicylic acid 0.9061025 0.1824408 G protein Phloretin 0.9164828 0.1797069 Ca2+ Channel Oxolinic acid 0.9179376 0.1793258 Antibiotic MRS 1754 0.9267975 0.1770158 Adenosine Guanfacine hydrochloride 0.9270566 0.1769486 Adrenoceptor Amiodarone hydrochloride 0.9292209 0.1763873 Adrenoceptor DNQX 0.9307443 0.1759929 Glutamate 4-Phenyl-3-furoxancarbonitrile 0.9313181 0.1758445 Nitric Oxide 5alpha-Pregnan-3alpha-ol-20-one 0.9335428 0.1752699 GABA SB 203186 0.9365314 0.1744998 Serotonin 1-(3-Chlorophenyl)piperazine dihydrochlonde 0.9515586 0.1706604 Serotonin U-83836 dihydrochloride 0.9540152 0.170038 Cell Stress Ketotifen fumarate 0.9572878 0.169211 Histamine Phaclofen 0.9701101 0.1659958 GABA Mianserin hydrochloride 0.9745504 0.1648917 Serotonin (6R)-5,6,7,8-Tetrahydro-L-biopterin hydrochloride 0.9757437 0.1645957 Neurotrausmission Quipazine, 6-nitro-, maleate 0.9781608 0.1639974 Serotonin L-azetidine-2-carboxylic acid 0.983687 0.1626347 Biochemistry Betaxolol hydrochloride 0.983822 0.1626015 Adrenoceptor D(−)-2-Amino-7-phosphonoheptanoic acid 0.9854635 0.1621982 Glutamate Pyrilamine maleate 0.9892572 0.1612687 Histamine GR 113808 0.9919556 0.1606096 Serotonin (B1)-Verapamil hydrochloride 1.008291 0.1566574 Ca2+ Channel N-Acetyltryptamine 1.0201218 0.1538353 Melatonin Furafylline 1.0246268 0.1527697 Biochemistry 4-Hydroxyphenethylamine hydrochloride 1.029835 0.1515437 Dopamine BW 245C 1.0357188 0.1501667 Prostanoids Clonidine hydrochloride 1.0408277 0.1489778 Adrenoceptor 4-Methylpyrazole hydrochloride 1.0424145 0.1486098 Biochemistry 8-(p-Sulfophenyl)theophylline 1.0468466 0.1475852 Adenosine ICI 118,551 hydrochloride 1.1005464 0.1355471 Adrenoceptor PPADS 1.1058077 0.1344049 P2 Receptor Acetazolamide 1.1110935 0.133264 Biochemistry SC-560 1.11293 0.1328693 Prostaglandin Carbamazepine 1.1144028 0.1325532 Anticonvulsant NF 023 1.1146556 0.132499 P2 Receptor Hydroxyurea 1.131284 0.1289678 DNA Metabolism (−)-MK-801 hydrogen maleate 1.1329541 0.1286168 Glutamate 2-Chloroadenosine triphosphate tetrasodium 1.1488299 0.1253131 P2 Receptor (B1)-HA-966 1.1567873 0.1236796 Glutamate (B1)-PD 128,907 hydrochloride 1.1639888 0.1222143 Dopamine BU99006 1.1815218 0.1186977 Imidazoline Rp-cAMPS triethylamine 1.185648 0.1178807 Phosphorylation (−)-alpha-Methylnorepinephrine 1.1934634 0.116344 Adrenoceptor 6-Hydroxy-DL-DOPA 1.2039428 0.1143058 Adrenoceptor 1-Phenyl-3-(2-thiazolyl)-2-thiourea 1.2082172 0.1134819 Dopamine Trihexyphenidyl hydrochloride 1.2149684 0.1121891 Cholinergic 8-(4-Chlorophenylthio)-cAMP sodium 1.216597 0.1118788 Cyclic Nucleotides Neostigmine bromide 1.2283216 0.1096631 Cholinergic Cyproheptadine hydrochloride 1.2319756 0.1089791 Serotonin (2S,1$$S,2$$S)-2-(carboxycyclopropyl)glycine 1.2330432 0.1087798 Glutamate 3-Aminopropionitrile fumarate 1.2343921 0.1085284 Multi-Drug Resistance 7-Chlorokynurenic acid 1.2408477 0.107331 Glutamate 1-Deoxynojirimycin hydrochloride 1.2419225 0.1071326 Biochemistry Atropine sulfate 1.2441828 0.1067161 Cholinergic Tryptamine hydrochloride 1.2448961 0.106585 Serotonin (B1)-2-Amino-3-phosphonopropionic acid 1.2497911 0.1056879 Glutamate S(−)-Willardiine 1.2513159 0.1054096 Glutamate U-99194A maleate 1.2553247 0.1046805 Dopamine Spermidine trihydrochloride 1.2585531 0.1040959 Glutamate Capsazepine 1.2598653 0.103859 Vanilloid (B1)-SKF-38393 hydrochloride 1.2798286 0.1003027 Dopamine gamma-Acetylinic GABA 1.2846402 0.099459 GABA Atropine methyl nitrate 1.2915005 0.0982651 Cholinergic Caffeic acid phenethyl ester 1.3062704 0.0957303 Cell Cycle PRE-084 1.3114125 0.0948592 Opioid (B1)-Taxifolin 1.3206971 0.0933012 Cell Stress Ro 41-1049 hydrochloride 1.3277095 0.0921371 Neurotransmission Dihydrokainic acid 1.3286819 0.0919765 Glutamate Dopamine hydrochloride 1.3517313 0.0882306 Dopamine SB 218795 1.3590835 0.0870601 Neurotransmission MJ33 1.364155 0.0862594 Lipid R(+)-SCH-23390 hydrochloride 1.3752617 0.0845252 Dopamine 5,5-Diphenylhydantoin 1.3825713 0.0833982 Anticonvulsant CP55940 1.3959333 0.0813673 Cannabinoid Sphingosine 1.4041813 0.0801324 Phosphorylation Dicyclomine hydrochloride 1.4143858 0.0786243 Cholinergic Tolazamide 1.4309708 0.0762193 Hormone A-77636 hydrochloride 1.4402256 0.0749018 Dopamine Bromoacetyl alprenolol menthane 1.4421969 0.0746234 Adrenoceptor 3,7-Dimethyl-I-propargylxanthine 1.453698 0.073015 Adenosine 2,2$$-Bipyridyl 1.4548052 0.0728616 Biochemistry L-Cysteinesulfinic Acid 1.4577326 0.0724571 Glutamate (B1)-Octoclothepin maleate 1.4730361 0.0703706 Dopamine GW9662 1.4746331 0.0701556 Transcription Phenamil methanesulfonate 1.4847913 0.0687996 Na+ Channel Ethylene glycol-bis(2-aminoethylether)-N,N,N$$,N$$-tetraacetic acid 1.5069032 0.0659177 Biochemistry Ivermectin 1.5073937 0.0658549 Cholinergic Prilocaine hydrochloride 1.5088803 0.0656647 Na+ Channel Benzamidine hydrochloride 1.509442 0.0655929 Biochemistry Tyrphostin AG 698 1.5101362 0.0655043 Phosphorylation AA-861 1.5165016 0.0646963 Leukotriene DSP-4 hydrochloride 1.5180671 0.0644987 Adrenoceptor Clorgyline hydrochloride 1.5204874 0.0641943 Neurotransmission Cisplatin 1.522768 0.0639084 DNA R(+)-6-Bromo-APB hydrobromide 1.5322395 0.0627317 Dopamine Olomoucine 1.5528427 0.0602304 Phosphorylation Molsidomine 1.5665706 0.0586075 Nitric Oxide Dextrorphan D-tartrate 1.5687122 0.0583575 Glutamate Astaxanthin 1.57146 0.0580379 Cell Stress Fluspirilene 1.5892579 0.0560011 Dopamine R(−)-SCH-12679 maleate 1.6092 0.0537863 Dopamine Hydroxylamine hydrochloride 1.6346899 0.051057 Neurotransmission Mizoribine 1.642204 0.0502739 DNA Metabolism Icilin 1.6433351 0.0501568 Neurotransmission Cimetidine 1.6653496 0.0479215 Histamine 5-Carboxamidotryptamine maleate 1.6674691 0.0477106 Serotonin Risperidone 1.6943795 0.0450966 Dopamine TMB-8 hydrochloride 1.7065885 0.0439493 Intracellular Calcium Picotamide 1.7355934 0.0413179 Thromboxane Doxylamine succinate 1.7361393 0.0412696 Histamine 3-deazaadenosine 1.7700481 0.0383596 Immune System 1-(m-Chlorophenyl)-biguanide hydrochloride 1.795282 0.0363044 Serotonin Sepiapterin 1.7953942 0.0362955 Nitric Oxide Tyrphostin AG 490 1.801543 0.0358087 Phosphorylation Apigenin 1.8240934 0.034069 Cell Cycle NF449 octasodium salt 1.8514998 0.0320488 G protein Methiothepin mesylate 1.8677893 0.0308957 Serotonin Nicardipine hydrochloride 1.8689406 0.0308155 Ca2+ Channel Tyrphostin AG 1478 1.8698642 0.0307513 Phosphorylation 5-(N-Methyl-N-isobutyl)amiloride 1.8712718 0.0306537 Ion Pump 4-Amino-1,8-naphthalimide 1.8746499 0.0304205 Apoptosis Furosemide 1.8888424 0.0294565 Ion Pump (B1)-2-Amino-4-phosphonobutyric acid 1.8932302 0.0291636 Glutamate S(+)-Raclopride L-tartrate 1.901273 0.0286331 Dopamine Methylcarbamylcholine chloride 1.9129289 0.0278786 Cholinergic Naloxone benzoylhydrazone 1.9153086 0.0277266 Opioid N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide 1.9158209 0.0276939 Benzodiazepine Androsterone 1.9472383 0.0257531 Hormone Reactive Blue 2 2.0032905 0.0225731 P2 Receptor 1,3-Diethyl-8-phenylxanthine 2.0054443 0.0224578 Adenosine Fusidic acid sodium 2.0449995 0.0204275 Cell Cycle SCH-28080 2.1072615 0.0175475 Ion Channels Danazol 2.1516479 0.0157125 Hormone Calcimycin 2.1716239 0.014942 Intracellular Calcium Bay 11-7085 2.1795367 0.0146459 Cell Cycle Carmustine 2.190861 0.0142309 DNA 1,3-PBIT dihydrobromide 2.2214777 0.0131593 Nitric Oxide Ceftriaxone sodium 2.2296212 0.0128863 Antibiotic Tyrphostin AG 835 2.2299784 0.0128744 Phosphorylation Cystamine dihydrochloride 2.229998 0.0128738 Glutamate Meclofenamic acid sodium 2.2325388 0.0127897 Prostaglandin Cephalothin sodium 2.263955 0.0117884 Antibiotic Suramin hexasodium 2.2844155 0.0111736 P2 Receptor 8-Bromo-cAMP sodium 2.3091105 0.0104687 Cyclic Nucleotides Tetraethylthiuram disulfide 2.3469984 0.0094627 Biochemistry WIN 62,577 2.3505544 0.0093727 Tachykinin 5-(N,N-Dimethyl)amiloride hydrochloride 2.396012 0.0082873 Ion Pump Sodium nitroprusside dihydrate 2.4043321 0.008101 Nitric Oxide SB 200646 hydrochloride 2.4372612 0.0073995 Serotonin L-3,4-Dihydroxyphenylalanine 2.4397458 0.0073488 Dopamine Cefmetazole sodium 2.5033943 0.0061504 Antibiotic MDL 105,519 2.56506 0.0051579 Glutamate 5-Bromo-2$$-deoxyuridine 2.5800017 0.00494 DNA Metabolism Nordihydroguaiaretic acid from Larrea divaricata (creosote bush) 2.6297007 0.004273 Leukotriene Tetramisole hydrochloride 2.6487799 0.0040391 Phosphorylation Pregnenolone sulfate sodium 2.6531789 0.0039869 GABA Clemizole hydrochloride 2.7881997 0.0026501 Histamine NCS-356 2.8326918 0.0023079 GABA (Z)-Gugglesterone 3.204847 0.0006757 Lipid Signaling R(+)-Atenolol 3.7643209 8.35E−05 Adrenoceptor Leflunomide 4.1031017 2.04E−05 Immune System LFM-A13 4.4998422 3.40E−06 Phosphorylation 1,3-Dipropyl-8-p-sulfophenylxanthine 4.7426719 1.05E−06 Adenosine Product Name Action Selectivity L-745,870 hydrochloride Antagonist D4 NS 521 oxalate Modulator Benzimidazolone Pentamidine isethionate Antagonist NMDA Rotenone Modulator Mitochondria Taxol Inhibitor Tubulin Apomorphine hydrochloride hemihydrate Agonist Amsacrine hydrochloride Inhibitor TopoII Brefeldin A from Penicillium brefeldianum Inhibitor Golgi apparatus Cytosine-1-beta-D-arabinofuranoside hydrochloride Inhibitor Dequalinium analog, C-14 linker Inhibitor PKC-alpha (+)-Butaclamol hydrochloride Antagonist GBR-12935 dihydrochloride Inhibitor Reuptake Idarubicin Inhibitor ML-7 Inhibitor MLCK Purvalanol A Inhibitor CDK Podophyllotoxin Inhibitor N,N,N-trimethyl-1-(4-trans-stilbenoxy)-2-propylammonium iodide Antagonist Nicotinic (B1)-7-Hydroxy-DPAT hydrobromide Agonist D3 Etoposide Inhibitor Topo II Perphenazine Antagonist DRD2 NG-Hydroxy-L-arginine acetate Metabolite NOS GBR-12909 dihydrochloride Inhibitor Reuptake Vincristine sulfate Inhibitor Tubulin Colchicine Inhibitor Tubulin PAPP Agonist 5-HT1A Chelerythrine chloride Inhibitor PKC MG 624 Antagonist Nicotinic Tamoxifen citrate Inhibitor PKC Hexamethonium dichloride Antagonist Nicotinic Emetine dihydrochloride hydrate Activator Ro 25-6981 hydrochloride Antagonist NMDA-NR2B beta-Lapachone Activator 2,3-Dimethoxy-1,4-naphthoquinone Modulator 2-Methylthioadenosine diphosphate trisodium Agonist P2Y Mitoxantrone Inhibitor Methotrexate Inhibitor Fluphenazine dihydrochloride Antagonist D1/D2 Naloxone hydrochloride Antagonist Diphenyleneiodonium chloride Inhibitor eNOS Sanguinarine chloride Inhibitor Na+/K+ ATPase Dihydrocapsaicin Agonist Ancitabine hydrochloride Inhibitor Arecaidine propargyl ester hydrobromide Agonist M2 R(−)-Apocodeine hydrochloride Agonist Aminopterin Inhibitor Dihydrofolate reductase Oligomycin A Inhibitor . Quinacrine dihydrochloride Inhibitor MAO 4′-Chloro-3-alpha-(diphenylmethoxy)tropane hydrochloride Blocker Reuptake (S)-(+)-Camptothecin Inhibitor TopoI Sobuzoxane Inhibitor Topo II Thapsigargin Releaser Dequalinium dichloride Blocker Vinblastine sulfate salt Inhibitor Tubulin XK469 Inhibitor TopoII beta ML-9 Inhibitor MLCK Trifluoperazine dihydrochloride Antagonist D1/D2 3-Tropanyl-3,5-dichlorobenzoate Antagonist 5-HT3 Raloxifene hydrochloride Modulator ER L-687,384 hydrochloride Agonist sigma1 CGP-74514A hydrochloride Inhibitor Cdk1 alpha-Guanidinoglutaric acid Inhibitor NOS N-Vanillylnonanamide Ligand U-74389G maleate Inhibitor Ganciclovir Inhibitor G2-M checkpoint Ifenprodil tartrate Blocker Polyamine site NMDA cis-(Z)-Flupenthixol dihydrochloride Antagonist Iodoacetamide Inhibitor (−)Amethopterin Inhibitor Calmidazolium chloride Inhibitor Ca2+ATPase Ellipticine Inhibitor CYP1A1/TopoII R(−)-Propylnorapomorphine hydrochloride Agonist DRD2 Metolazone Inhibitor Na+/Cl− transporter Carbetapentane citrate Ligand sigma1 Azathioprine Inhibitor Purine synthesis R(−)-N-Allylnorapomorphine hydrobromide Agonist 5-Fluorouracil Inhibitor Thymidylate synthetase 3-Methoxy-morphanin hydrochloride Antagonist Methoctramine tetrahydrochloride Antagonist M2 2-(alpha-Naphthoyl)ethyltrimethylammonium iodide Inhibitor Choline Acetyltransferase 3-Amino-1-propanesulfonic acid sodium Agonist GABA-A Mevastatin Inhibitor Ras, Rho Carboplatin Intercalator Retinoic acid p-hydroxyanilide Inhibitor (B1)-Butaclamol hydrochloride Antagonist D2 > D1 SB 204070 hydrochloride Antagonist 5-HT4 S-(−)-Eticlopride hydrochloride Antagonist DRD2 3′-Azido-3′-deoxythymidine Inhibitor Reverse transcriptase Chlorprothixene hydrochloride Antagonist DRD2 Metaphit methanesulfonate Antagonist sigma SB 224289 hydrochloride Antagonist 5-HT1B Triamterene Blocker N-Acetylprocainamide hydrochloride Blocker Guanidinoethyl disulfide dihydrobromide Inhibitor iNOS SKF 96365 Inhibitor R(−)-Denopamine Agonist beta1 Metergoline Antagonist 5-HT2/5-HT1D Disopyramide Blocker (+)-Brompheniramine maleate Antagonist HRH1 Cephalexin hydrate Cell wall synthesis DL-alpha-Methyl-p-tyrosine Inhibitor Tyrosine hydroxylase Melphalan Intercalator GCC CNS-1102 Antagonist NMDA Benztropine mesylate Antagonist Muscarinic (B1)-Brompheniramine maleate Antagonist HRH1 Actinonin Inhibitor Leucine aminopeptidase Protoporphyrin IX disodium Activator Guanylyl cyclase (+)-cis-Dioxolane iodide Agonist Muscarinic Indomethacin morpholinylamide Ligand CB2 Ketanserin tartrate Antagonist 5-HT2 Cephalosporin C zinc salt Cell wall synthesis R(−)-2,10,11-Trihydroxyaporphine hybrobromide Agonist DRD2 Methoxamine hydrochloride Agonist alpha1 Chlorothiazide Inhibitor Carbonic anhydrase Hydrocortisone Cortisol 7,7-Dimethyl-(5Z,8Z)-eicosadienoic acid Inhibitor PLA2/Lipoxygenase Cefaclor Cell wall synthesis Daidzein Inhibitor Aldehyde dehydrogenase Prazosin hydrochloride Antagonist alpha1 Z-L-Phe chloromethyl ketone Inhibitor Chymotrypsin A-gamma N6-Cyclohexyladenosine Agonist A1 SB 415286 Inhibitor GSK-3 (B1) trans-U-50488 methanesulfonate Agonist kappa Isoliquiritigenin Activator Guanylyl cyclase Niclosamide Protonophore BRL 52537 hydrochloride Agonist kappa/mu opioid R(−)-2,10,11-Trihydroxy-N-propylnoraporphine hydrobromide Agonist DRD2 Oxymetazoline hydrochloride Agonist alpha2A S(−)-UH-301 hydrochloride Antagonist 5-HT1A 1-Phenylbiguanide Agonist 5-HT3 NS 2028 Inhibitor Guanylate cyclase SDZ-205,557 hydrochloride Antagonist 5-HT4 Betaine hydrochloride Metabolite 6-Methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4b] indole Inhibitor MAO Pergolide methanesulfonate Agonist D2/D1 Bepridil hydrochloride Blocker (−)-Sulpiride Antagonist DRD2 Trazodone hydrochloride Inhibitor Reuptake R-(+)-7-Hydroxy-DPAT hydrobromide Agonist D3 5′-N-Ethylcarboxamidoadenosine Agonist A1/A2 5′-N-Methyl carboxamidoadenosine Agonist A2 > A1 3′,4′-Dichlorobenzamil Inhibitor Na+/Ca2+ exchanger Cefazolin sodium Cell wall synthesis CGS-12066A maleate Agonist 5-HT1B m-Iodobenzylguanidine hemisulfate Activator SB 216763 Inhibitor GSK-3 R(+)-UH-301 hydrochloride Agonist 5-HT1A 1-(2-Chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane Inhibitor Corticosteroid Zaprinast Inhibitor PDE V HE-NECA Agonist A2 Noscapine hydrchloride Ligand Dubinidine Quinolinic acid Antagonist NMDA 1-Aminocyclopropanecarboxylic acid hydrochloride Agonist NMDA-Glycine Nimesulide Inhibitor COX-2 (B1)-AMT hydrochloride Inhibitor iNOS 2-Chloro-2-deoxy-D-glucose Analog Glucose Efaroxan hydrochloride Antagonist I1 L-2-aminoadipic acid Inhibitor Glutamine synthetase Ritodrine hydrochloride Agonist beta2 3-Aminopropylphosphonic acid Agonist GABA-B Tyrphostin AG 34 Inhibitor Tyrosine kinase S-(−)-Carbidopa Inhibitor Aromatic amino acid decarboxylase Quercetin dihydrate Inhibitor PDE SB 204741 Antagonist 5-HT2B cis-(B1)-8-OH-PBZI hydrobromide Agonist D3 Praziquantel Ca2+ Ionophore Corticosterone Glucocorticoid Cefsulodin sodium salt hydrate Cell wall synthesis Tyrphostin AG 494 Inhibitor EGFR (B1)-6-Chloro-PB hydrobromide Agonist D1 Gabaculine hydrochloride Inhibitor GABA transaminase (B1)-2,3-Dichloro-alpha-methylbenzylamine hydrochloride Inhibitor PNMT cis-Azetidine-2,4-dicarboxylic acid Modulator NMDA WB-4101 hydrochloride Antagonist alpha1A Acetohexamide Releaser Insulin (+)-Nicotine (+)-di-p-toluoyl tartrate Agonist Nicotinic Isoguvacine hydrochloride Agonist GABA-A, GABA-C Cortisone 21-acetate Cortisol Morin Inhibitor Antioxidant R(+)-3PPP hydrochloride Agonist DRD2 Serotonin hydrochloride Agonist Ro 8-4304 Antagonist NMDA-NR2B Bumetanide Inhibitor Na+-K+-2Cl-cotransporter Ro 16-6491 hydrochloride Inhibitor MAO-B 6-Aminohexanoic acid Inhibitor Blood Clotting 1-Allyl-3,7-dimethyl-8-p-sulfophenylxanthine Antagonist A2 Mesulergine hydrochloride Agonist p-MPPF dihydrochloride Antagonist 5-HT1A TTNPB Ligand RAR-alpha, beta, gamma (E)-4-amino-2-butenoic acid Agonist GABA-C D-ribofuranosylbenzimidazole Inhibitor Alprenolol hydrochloride Antagonist beta (E)-5-(2-Bromovinyl)-2′-deoxyuridine Inhibitor HSV1 Pinacidil Activator (B1)-Chlorpheniramine maleate Antagonist HRH1 Fenofibrate Agonist PPAR-alpha N6-Cyclopentyl-9-methyladenine Antagonist A1 Mecamylamine hydrochloride Antagonist Nicotinic Ranolazine dihydrochloride Inhibitor pFOX Lorglumide sodium Antagonist CCK-A Rolipram Inhibitor PDE IV 4-Imidazolemethanol hydrochloride Inhibitor Histinol Dehydrogenase PPNDS tetrasodium Antagonist P2X1 U-101958 maleate Antagonist D4 O-(Carboxymethyl)hydroxylamine hemihydrochloride Inhibitor Aminotransferase Pyrocatechol Inhibitor 3-Phenylpropargylamine hydrochloride Inhibitor Dopamine beta-hydroxylase Clemastine fumarate Antagonist HRH1 R(−)-N6-(2-Phenylisopropyl)adenosine Agonist A1 T-1032 Inhibitor PDE V DM 235 TCPOBOP Agonist CAR R(+)-Terguride Agonist Budesonide Cortisol Metoclopramide hydrochloride Antagonist DRD2 SP600125 Inhibitor c-JNK Mifepristone Antagonist Progesterone (B1)-Vesamicol hydrochloride Inhibitor ACh storage Niflumic acid Inhibitor COX-2 Acetamide Inhibitor Carbonic anhydrase Succinylcholine chloride Antagonist Nicotinic Quinidine sulfate Antagonist SKF-525A hydrochloride Inhibitor Microsomal oxidation (B1)-PPHT hydrochloride Agonist DRD2 Proglumide Antagonist IMID-4F hydrochloride Blocker Guanabenz acetate Agonist alpha2 (B1)-Muscarine chloride Agonist Muscarinic CNQX disodium Antagonist AMPA/Kainate Thiothixene hydrochloride Antagonist D1/D2 (B1)-3-(3,4-dihydroxyphenyl)-2-methyl-DL-alanine Inhibitor L-aromatic amino acid decarhoxylase 2′,3′-didehydro-3′-deoxythymidine Inhibitor Reverse Transcriptase (−)-Tetramisole hydrochloride Inhibitor GYKI 52466 hydrochloride Antagonist AMPA/kainate Doxazosin mesylate Blocker alpha1 N-Methyl-D-aspartic acid Agonist NMDA Citalopram hydrobromide Inhibitor Reuptake (−)-Bicuculline methbromide, 1(S), 9(R) Antagonist GABA-A Fenoterol hydrobromide Agonist beta2 Loratadine Antagonist HRH1 Triflupromazine hydrochloride Antagonist DRD2 (B1)-Vanillylmandelic acid Metabolite 2,3-Butanedione monoxime Blocker ATP-sensitive AL-8810 Antagonist FP Receptor Cyproterone acetate Antagonist Androgen L-alpha-Methyl-p-tyrosine Inhibitor Tyrosine hydroxylase (B1)-Normetanephrine hydrochloride Metabolite Norepinephrine Carisoprodol Skeletal muscle Dihydro-beta-erythroidine hydrobromide Antagonist nAch Diacylglycerol kinase inhibitor I Inhibitor Diacylglycerol kinase Buspirone hydrochloride Agonist 5-HT1A Tulobuterol hydrochloride Agonist beta SIB 1757 Antagonist mGluR5 S-Methyl-L-thiocitrulline acetate Inhibitor NOS Rauwolscine hydrochloride Antagonist alpha2 Tyrphostin A9 Inhibitor PDGFR Clofibrate Modulator Lipoprotein lipase NCS-382 Antagonist gamma-Hydroxybutyrate N,N-Dipropyl-5-carboxamidotryptamine maleate Agonist 5-HT1A BRL 37344 sodium Agonist beta3 Naphazoline hydrochloride Agonist alpha Pempidine tartrate Antagonist Nicotinic BP 897 Agonist D3 E-64 Inhibitor Cysteine protease 5′-(N-Cyclopropyl)carboxamidoadenosine Agonist A2 SB 222200 Antagonist NK3 WB 64 Ligand M2 ATPO Antagonist GluR1-4 3-Bromo-7-nitroindazole Inhibitor NOS Salbutamol Agonist beta2 NBQX disodium Antagonist AMPA/kainate 5-Aminovaleric acid hydrochloride Antagonist GABA-B OXA-22 iodide Agonist Muscarinic 5,5-Dimethyl-1-pyrroline-N-oxide Inhibitor Antioxidant 6-Chloromelatonin Agonist Yohimbine hydrochloride Antagonist alpha2 (B1)-Ibotenic acid Agonist NMDA S-Nitroso-N-acetylpenicillamine Donor 2,3-Butanedione Inhibitor Myosin ATPase SC 19220 Antagonist EP1 Pentoxifylline Inhibitor PDE IC 261 Inhibitor CK-1delta/epsilon Karakoline Antagonist Nicotinic 2-Hydroxysaclofen Antagonist GABA-B Trifluperidol hydrochloride Antagonist D1/D2 N-Acetyl-L-Cysteine Antagonist Pyrazinecarboxamide (B1)-CGP-12177A hydrochloride Agonist beta N-Phenylanthranilic acid Blocker Nitrendipine Antagonist L-type Tyrphostin AG 527 Inhibitor EGFR Tyrphostin AG 879 Inhibitor TrkA S-Ethylisothiourea hydrobromide Inhibitor NOS (B1)-SKF 38393, N-allyl-, hydrobromide Agonist D1 Propionylpromazine hydrochloride Antagonist DRD2 1-(4-Chlorobenzyl)-5-methoxy-2-methylindole-3-acetic acid Inhibitor MRP1 H-8 dihydrochloride Inhibitor PKA, PKG Decamethonium dibromide Agonist Nicotinic p-Benzoquinone Inhibitor G:C site Ouabain Inhibitor Na+/K+ ATPase (B1)-Octopamine hydrochloride Agonist alpha Quinelorane dihydroechloride Agonist DRD2 (−)-Quinpirole hydrochloride Agonist D2/D3 Kenpaullone Inhibitor CDK1, CDK2, CDK5 MK-886 Inhibitor SR 2640 Antagonist CysLT1 (+)-Pilocarpine hydrochloride Agonist Muscarinic 10-(alpha-Diethylaminopropionyl)-phenothiazine hydrochloride Inhibitor Butyrylcholinesterase Aminophylline ethylenediamine Antagonist A1/A2 Phenelzine sulfate Inhibitor MAO-A/B Propantheline bromide Antagonist Muscarinic 3-Tropanyl-indole-3-carboxylate hydrochloride Antagonist 5-HT3 Domperidone Antagonist DRD2 PD 168,077 maleate Agonist D4 4-Aminopyridine Blocker A-type Phenoxybenzamine hydrochloride Blocker alpha Flecainide acetate Blocker Chlorzoxazone Inhibitor iNOS Hexahydro-sila-difenidol hydrochloride, p-fluoro analog Antagonist M3 > M1 > M2 R(−)-Isoproterenol (+)-bitartrate Agonist beta Pirfenidone Inhibitor Histamine dihydrochloride Agonist Histamine, R(−)-alpha-methyl-, dihydrochloride Agonist H3 13-cis-retinoic acid Regulator RAR-alpha, beta L-733,060 hydrochloride Antagonist NK1 Aminobenztropine Ligand Muscarinic Idazoxan hydrochloride Ligand I1/I2 Quipazine dimaleate Agonist Tranylcypromine hydrochloride Inhibitor MAO Cortexolone maleate Antagonist DRD2 L-Histidine hydrochloride Precursor SB-366791 Antagonist VR1 L(−)-Norepinephrine bitartrate Agonist alpha, beta1 R(−)-Me5 Antagonist 7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4- Inhibitor Ick ylamine NG-Nitro-L-arginine methyl ester hydrochloride Inhibitor NOS (B1)-Methoxyverapamil hydrochloride Antagonist L-type Semicarbazide hydrochloride Inhibitor MAO Harmane Agonist I1 Phosphomycin disodium Cell wall synthesis SR 57227A Agonist 5-HT3 5-azacytidine Inhibitor DNA methyltransferase Theobromine Antagonist A1 > A2 beta-Chloro-L-alanine hydrochloride Inhibitor Alanine aminotransferase Diacylglycerol Kinase Inhibitor II Inhibitor Diacylglycerol kinase NG-Monomethyl-L-arginine acetate Inhibitor NOS Nylidrin hydrochloride Agonist beta Cinnarizine Blocker N{circumflex over ( )}G, N{circumflex over ( )}G-Dimethylarginine hydrochloride Inhibitor NOS 2′,3′-dideoxycytidine Inhibitor Reverse Transcriptase SB 206553 hydrochloride Antagonist 5-HT2C/5-HT2B N-Bromoacetamide Modulator Sulfaphenazole Inhibitor Cytochrome P4502C SKF 83959 hydrobromide Agonist D1 Aniracetam Agonist AMPA 7-Nitroindazole Inhibitor nNOS Dipropyldopamine hydrobromide Agonist Guvacine hydrochloride Inhibitor Uptake (B1)-DOI hydrochloride Agonist 5-HT2/5-HT1C N-Methyl-1-deoxynojirimycin Inhibitor Glucosidase Forskolin Activator Adenylate cyclase Ciprofibrate Ligand PPAR-alpha Methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate Agonist 3-Morpholinosydnonimine hydrochloride Donor N6-2-(4-Aminophenyl)ethyladenosine Agonist A3 Luteolin Inhibitor Antioxidant Altretamine Inhibitor (−)-Perillic acid Inhibitor p21 Ras Tyrphostin AG 808 Inhibitor Tyrosine kinase Fluoxetine hydrochloride Inhibitor Reuptake 5-Hydroxyindolacetic acid Metabolite Thiolactomycin Inhibitor Myristate synthesis S(−)-p-Bromotetramisole oxalate Inhibitor Alkaline phosphatase alpha,beta-Methylene adenosine 5′-triphosphate dilithium Agonist P2X > P2Y 4-Aminobenzamidine dihydrochloride Inhibitor Trypsin Captopril Inhibitor ACE B-HT 933 dihydrochloride Agonist alpha2 DBO-83 Agonist Nicotinic (+)-Chlorpheniramine maleate Antagonist HRH1 rac-2-Ethoxy-3-hexadecanamido-1-propylphosphocholine Inhibitor PKC Mexiletene hydrochloride Blocker GYKI 52895 Inhibitor Reuptake Phenylephrine hydrochloride Agonist alpha1 2-(2-Aminoethyl)isothiourea dihydrobromide Inhibitor NOS Norcantharidin Inhibitor PP2A Tyrphostin AG 537 Inhibitor EGFR MRS 2179 Antagonist P2Y1 N-(3,3-Diphenylpropyl)glycinamide Blocker NMDA D-Cycloserine Agonist NMDA-Glycine Trimethoprim Inhibitor Dihydrofolate reductase CGS-21680 hydrochloride Agonist A2a SR 59230A oxalate Antagonist beta3 Aminoguanidine hemisulfate Inhibitor NOS N-Methyldopamine hydrochloride Agonist LY-294,002 hydrochloride Inhibitor PI3K Acyclovir Inhibitor Viral DNA synthesis 8-(3-Chlorostyryl)caffeine Antagonist A2A Pilocarpine nitrate Agonist Muscarinic U-73122 Inhibitor PLC, A2 Ribavirin Inhibitor IMP dehydrogenase Minoxidil Activator ATP sensitive Adenosine 3′,5′-cyclic monophosphate Activator PKA REV 5901 Antagonist LTD4 L-750,667 trihydrochloride Antagonist D4 1,4-PBIT dihydrobromide Inhibitor NOS O6-benzylguanine Inhibitor . S(+)-PD 128,907 hydrochloride Agonist D3 6-Fluoronorepinephrine hydrochloride Agonist alpha Ketoprofen Inhibitor COX-1 Monastrol Inhibitor EgG5 TEPI hydrochloride Inhibitor nNOS L-allylglycine Inhibitor . Endothall Inhibitor PP2A Meloxicam sodium Inhibitor COX-2 MDL 28170 Inhibitor Calpain I/II SB 202190 Inhibitor p38 MAPK S(−)-Pindolol Agonist 5-HT1A 3,4-Dichloroisocoumarin Inhibitor Serine Protease Tetraisopropyl pyrophosphoramide Inhibitor Butyrylcholinesterase rac-2-Ethoxy-3-octadecanamido-1-propylphosphocholine Inhibitor PKC (B1)-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol Inhibitor Glucosylceramide synthase hydrochloride SB 269970 hydrochloride Antagonist 5-HT7 FPL 64176 Activator L-type NSC 95397 Inhibitor Cdc25 Labetalol hydrochloride Antagonist beta CGP-13501 Modulator GABA-B Cefotaxime sodium Cell wall synthesis Nortriptyline hydrochloride Inhibitor Uptake Lamotrigine Cinoxacin Inhibitor 3-n-Propylxanthine Antagonist A1 > A2 IB-MECA Agonist A3 cis-4-Aminocrotonic acid Agonist GABA-C CB34 Ligand GR 127935 hydrochloride Antagonist 5-HT1B/1D LY-278,584 maleate Antagonist 5-HT3 2,6-Diamino-4-pyrimidinone Inhibitor GTP cyclohydrolase I CB 1954 Intercalator LE 300 Antagonist D1 (B1)-Baclofen Agonist GABA-B N-Acetyl-5-hydroxytryptamine Precursor 1,1-Dimethyl-4-phenyl-piperazinium iodide Agonist Benzamil hydrochloride Blocker Na+/H+, Na+/Ca2+ Pump (R,R)-cis-Diethyl tetrahydro-2,8-chrysenediol Antagonist ER-beta CX 546 Modulator AMPA (B1)-2-Amino-5-phosphonopentanoic acid Antagonist NMDA Amoxapine Inhibitor Uptake R(+)-Lisuride hydrogen maleate Agonist DRD2 3-aminobenzamide Inhibitor PARS Riluzole Antagonist Release Reserpine Inhibitor Uptake Carcinine dihydrochloride Inhibitor Antioxidant DL-Buthionine-[S,R]-sulfoximine Inhibitor Metaproterenol hemisulfate Agonist beta2 9-Amino-1,2,3,4-tetrahydroacridine hydrochloride Inhibitor Cholinesterase (B1)-2-Amino-7-phosphonoheptanoic acid Antagonist NMDA Moxisylyte hydrochloride Antagonist alpha1 Doxepin hydrochloride Inhibitor Uptake L-741,626 Antagonist DRD2 8-Bromo-cGMP sodium Activator CR 2249 Agonist NMDA-Glycine GW7647 Agonist PPAR-alpha Imiloxan hydrochloride Antagonist alpha2B 2-methoxyestradiol Metabolite Estrogen Daphnetin Inhibitor PK Cyclophosphamide monohydrate Intercalator Trequinsin hydrochloride Inhibitor PDE III Propafenone hydrochloride Blocker hKv1.5 Felodipine Blocker L-type S(−)-Pindolol Antagonist beta SR-95531 Antagonist GABA-A 1-benzoyl-5-methoxy-2-methylindole-3-acetic acid Inhibitor MRP1 Albuterol hemisulfate Agonist beta2 Chlormezanone Modulator Muscle relaxant L-N5-(1-Iminoethyl)ornithine hydrochloride Inhibitor NOS Pentylenetetrazole Modulator CNS N-(4-Aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride Antagonist Calmodulin Imidazole-4-acetic acid hydrochloride Antagonist GABA-C Tyrphostin 51 Inhibitor EGFR Zonisamide sodium Gallamine triethiodide Antagonist M2 Palmitoylethanolamide Agonist CB2 Myricetin Inhibitor Casein Kinase II Lithium Chloride Inhibitor Inositol monophosphatase Agroclavine Agonist Cyclothiazide Agonist AMPA L-Canavanine sulfate Inhibitor iNOS L-alpha-Methyl DOPA Inhibitor Aromatic amino acid decarboxylase D-609 potassium Inhibitor PIPLC BWB70C Inhibitor 5-lipoxygenase AC 915 oxalate Ligand sigmal Phosphonoacetic acid Inhibitor DNA Polymerase Promazine hydrochloride Antagonist DRD2 1,10-Phenanthroline monohydrate Inhibitor Metalloprotease loxoprofen Inhibitor COX Atropine methyl bromide Antagonist Muscarinic Retinoic acid Activator Prochlorperazine dimaleate Antagonist Nimodipine Antagonist L-type SIB 1893 Antagonist mGluR5 Chloro-IB-MECA Agonist A3 1-Methylimidazole Inhibitor COX (−)-Scopolamine methyl bromide Antagonist Muscarinic Clomipramine hydrochloride Inhibitor Reuptake Tyrphostin 23 Inhibitor EGFR Formoterol Agonist beta2 (+)-Hydrastine Antagonist GABA-A L-765,314 Antagonist alpha-1B Glipizide Blocker ATP-sensitive Ceramide Inhibitor Diacylglycerol kinase Hexamethonium bromide Antagonist Nicotinic (B1)-Sotalol hydrochloride Antagonist beta S-(+)-Fluoxetine hydrochloride Inhibitor Reuptake 5alpha-Pregnan-3alpha-ol-11,20-dione Modulator GABA-A CPCCOEt Antagonist mGluR1 Edrophonium chloride Inhibitor Acetylcholinesterase Amiloride hydrochloride Blocker Epithelial N6-Benzyl-5′-N-ethylcarboxamidoadenosine Agonist A3 Dextromethorphan hydrobromide monohydrate Antagonist NMDA 4-Hydroxybenzhydrazide Inhibitor Epibestatin hydrochloride Inhibitor Metalloprotease Methylergonovine maleate Antagonist N6-Cyclopentyladenosine Agonist A1 Urapidil, 5-Methyl- Antagonist alpha1A alpha-Methyl-5-hydroxytryptamine maleate Agonist 5-HT2 Dihydroergotamine methanesulfonate Antagonist GR-89696 fumarate Agonist kappa Amiprilose hydrochloride Modulator 2-Methylthioadenosine triphosphate tetrasodium Agonist P2Y 3-Isobutyl-1-methylxanthine Inhibitor Phosphodiesterase Dihydroergocristine methanesulfonate Agonist Putrescine dihydrochloride Agonist NMDA-Polyamine S(−)-Timolol maleate Antagonist beta SKF 91488 dihydrochloride Inhibitor Histamine N-methyltransferase erythro-9-(2-Hydroxy-3-nonyl)adenine hydrochloride Inhibitor Adenosine deaminase VER-3323 hemifumarate salt Agonist 5-HT2C/5-HT2B Sodium Taurocholate Modulator Conjugate Pathway Iofetamine hydrochloride Analog Fexofenadine hydrochloride Antagonist HRH1 (S)-(−)-propafenone hydrochloride Blocker beta 1-Amino-1-cyclohexanecarboxylic acid hydrochloride Substrate Loxapine succinate Antagonist (−)-Scopolamine hydrobromide Antagonist Muscarinic Haloperidol Antagonist D2/D1 I-OMe-Tyrphostin AG 538 Inhibitor IGF-1 RTK SKF 97541 hydrochloride Agonist GABA-B 5-Nitro-2-(3-phenylpropylamino)benzoic acid Blocker S(+)-Ibuprofen Inhibitor COX Choline bromide Substrate Choline acetyltransferase U-69593 Agonist kappa Dipyridamole Inhibitor Ketorolac tris salt Inhibitor COX Parthenolide Inhibitor Indatraline hydrochloride Inhibitor Reuptake (B1)-Nipecotic acid Inhibitor Uptake Clotrimazole Inhibitor Ca2+-activated K+ channel p-Fluoro-L-phenylalanine Substrate Tyrosine Hydroxylase (B1)-gamma-Vinyl GABA Inhibitor Transaminase Oxotremorine methiodide Agonist Muscarinic Ritanserin Antagonist 5-HT2/5-HT1C 4-Androstene-3,17-dione Precursor Androgen R-(+)-8-Hydroxy-DPAT hydrobromide Agonist 5-HT1A HA-100 Inhibitor PKA/PKC/MLCK Lidocaine N-methyl hydrochloride Blocker Tyrphostin AG 555 Inhibitor EGFR (R)-(+)-WIN 55,212-2 mesylate Agonist 1,7-Dimethylxanthine Antagonist A1 > A2 SU 5416 Inhibitor VEGFR PTK Seglitide Agonist sst2 L-Hyoscyamine Antagonist BMY 7378 dihydrochloride Agonist 5-HT1A (B1)-Atenolol Antagonist beta1 Amantadine hydrochloride Releaser Nimustine hydrochloride Intercalator Bethanechol chloride Agonist Muscarinic Zimelidine dihydrochloride Inhibitor Reuptake Tyrphostin 1 Inhibitor EGFR N,N,N′,N′-Tetramethylazodicarboxamide Modulator Thiols Isotharine mesylate Agonist beta 1-(2-Methoxyphenyl)piperazine hydrochloride Agonist 5-HT1 > 5-HT2 ET-18-OCH3 Inhibitor PIPLC Enoximone Inhibitor PDE III NAN-190 hydrobromide Antagonist 5-HT1A L-655,708 Ligand GABA-A Oxiracetam Ethosuximide Cortexolone Precursor Cortisol Naloxonazine dihydrochloride Antagonist mu1 N-(4-Amino-2-chlorophenyl)phthalimide Cysteamine hydrochloride Depleter Vanillic acid diethylamide Agonist ODQ Inhibitor NO-sensitive guanylyl cyclase L-Glutamic acid, N-phthaloyl- Agonist NMDA L-Leucinethiol, oxidized dihydrochloride Inhibitor Aminopeptidase 3,4-Dihydroxyphenylacetic acid Metabolite MK-912 Agonist alpha2A Cortisone Corticosteroid 17alpha-hydroxyprogesterone Metabolite Progesterone Cantharidin Inhibitor PP2A Fenspiride hydrochloride Antagonist alpha 2-Cyelooctyl-2-hydroxyethylamine hydrochloride Inhibitor PNMT (B1)-Isoproterenol hydrochloride Agonist beta 4-Hydroxy-3-methoxyphenylacetic acid Metabolite 3-Nitropropionic acid Toxin beta-Estradiol Estrogen Etodolac Inhibitor COX Doxycycline hydrochloride Protein synthesis MHPG sulfate potassium Metabolite Cantharidic Acid Inhibitor PP1/PP2A (S)-MAP4 hydrochloride Antagonist mGluR4,6,7 Linopirdine Releaser Pireuzepine dihydrochloride Antagonist M1 1-(4-Fluorobenzyl)-5-methoxy-2-methylindole-3-acetic acid Inhibitor MRP1 (S)-Propranolol hydrochloride Blocker beta (−)-Epinephrine bitartrate Agonist 3,5-Dinitrocatechol Inhibitor COMT Imipramine hydrochloride Blocker Reuptake Spironolactone Antagonist Mineralocorticoid DL-threo-beta-hydroxyaspartic acid Inhibitor Transport Spiperone hydrochloride Antagonist DRD2 GW2974 Inhibitor EGFR/ErbB-2 (−)-Cotinine Metabolite Nicotinic Phosphoramidon disodium Inhibitor Endopeptidase L-703,606 oxalate Antagonist NK1 R-(−)-Desmethyldeprenyl hydrochloride Inhibitor MAO-B 2,6-Difluoro-4-[2-(phenylsulfonylamino)ethylthio]phenoxyacetamide Agonist AMPA Loperamide hydrochloride Ligand WAY-100635 maleate Antagonist 5-HT1A Salmeterol Agonist beta2 Ofloxacin DNA Synthesis NS-1619 Activator Ca2+ activated 3-Hydroxybenzylhydrazine dihydrochloride Inhibitor Amino acid decarboxylase Flupirtine maleate Antagonist NMDA Emodin Inhibitor p56lck TK Acetylsalicylic acid Inhibitor COX-3 > COX-1 > COX-2 (+)-trans-(1R,2R)-U-50488 hydrochloride Agonist kappa L-Glutamic acid hydrochloride Agonist Tetrahydrozoline hydrochloride Agonist alpha Genistein Inhibitor Tyrosine kinase PK 11195 Antagonist Benzodiazepine NO-711 hydrochloride Inhibitor Uptake Felbamate Antagonist Diethylenetriaminepentaacetic acid Inhibitor Zn2+-dependent protease SNC80 Agonist delta Isonipecotic acid Agonist GABA-A (B1)-Quinpirole dihydrochloride Agonist D2 > D3 (−)-Scopolamine methyl nitrate Antagonist Muscarinic (B1)-p-Aminoglutethimide Inhibitor P450-dependendent hydroxylation Alloxazine Antagonist A2b GABA Agonist CV-3988 Antagonist PAF (B1)-AMPA hydrobromide Agonist AMPA/kainate S-(4-Nitrobenzyl)-6-thioinosine Inhibitor Uptake DL-alpha-Difluoromethylornithine hydrochloride Inhibitor ODC Piperidine-4-sulphonic acid Agonist GABA-A S(−)-3PPP hydrochloride Agonist DRD2 Ammonium pyrrolidinedithiocarbamate Modulator NOS Dihydrexidine hydrochloride Agonist D1 N-(p-Isothiocyanatophenethyl)spiperone hydrochloride Antagonist DRD2 Amperozide hydrochloride Ligand N-Oleoylethanolamine Inhibitor Ceramidase CGP-7930 Modulator GABA-B Tyrphostin AG 126 Inhibitor TNFalpha LY-367,265 Antagonist Reuptake Triprolidine hydrochloride Antagonist HRH1 BW 284c51 Inhibitor Acetylcholinesterase 7-Chloro-4-hydroxy-2-phenyl-1,8-naphthyridine Antagonist A1 Indirubin-3′-oxime Inhibitor CDK 2-Chloroadenosine Agonist A1 > A2 Tyrphostin AG 538 Inhibitor IGF-1 RTK 5alpha-Androstane-3alpha, 17beta-diol Metabolite Androgen L-N6-(1-Iminoethyl)lysine hydrochloride Inhibitor iNOS Piracetam Modulator AMPA Flumazenil Antagonist ICI 204,448 hydrochloride Agonist kappa Maprotiline hydrochloride Inhibitor Reuptake Naltriben methanesulfonate Antagonist delta2 Glibenclamide Blocker ATP-dependent Ro 41-0960 Inhibitor COMT Indomethacin Inhibitor COX S-5-Iodowillardiine Agonist AMPA Bromoacetylcholine bromide Ligand IIK7 Agonist trans-Azetidine-2,4-dicarboxylic acid Agonist mGluR1, mGluR5 Levallorphan tartrate Antagonist Oleic Acid Activator PKC 3-Tropanylindole-3-carboxylate methiodide Antagonist 5-HT3 Zardaverine Inhibitor PDE III/PDE IV 8-Methoxymethyl-3-isobutyl-1-methylxanthine Inhibitor PDE I LY-53,857 maleate Antagonist 5-HT2/5-HT1C Acetyl-beta-methylcholine chloride Agonist M1 (S)-3,5-Dihydroxyphenylglycine Agonist mGluR1 Benazoline oxalate Agonist I2 Adenosine amine congener Agonist A1 Piribedil maleate Agonist D3 Centrophenoxine hydrochloride Arcaine sulfate Antagonist NMDA-Polyamine (B1)-Epinephrine hydrochloride Agonist Quipazine, N-methyl-, dimaleate Agonist 5-HT3 Tetradecylthioacetic acid Agonist PPAR-alpha Phentolamine mesylate Antagonist alpha Kainic acid Agonist Kainate Tracazolate Modulator Nalidixic acid sodium Inhibitor DNA Gyrase Naltrindole hydrochloride Antagonist delta DL-Thiorphan Inhibitor Enkephalinase Ipratropium bromide Antagonist Muscarinic Debrisoquin sulfate Antihypertensive Tolbutamide Releaser Insulin U-62066 Agonist kappa Papaverine hydrochloride Inhibitor PDE DL-Cycloserine Inhibitor Ketosphinganine synthase, Alanine aminotransferase (−)-trans-(1S,2S)-U-50488 hydrochloride Agonist kappa S(+)-Isoproterenol (+)-bitartrate beta Nifedipine Antagonist L-type 5-(N-Ethyl-N-isopropyl)amiloride Blocker Na+/H+ Antiporter P1,P4-Di(adenosine-5′)tetraphosphate triammonium Inhibitor JL-18 Antagonist D4 > D2 (B1)-Sulpiride Antagonist DRD2 Pargyline hydrochloride Inhibitor MAO-B 1400W dihydrochloride Inhibitor iNOS (B1)-Metoprolol (+)-tartrate Antagonist beta1 Quinine sulfate Antagonist MRS 2159 Antagonist P2X1 Phorbol 12-myristate 13-acetate Activator PKC 4-Imidazoleacrylic acid Inhibitor Histidine ammonia-lyase/ decarboxylase (B1)-Ibuprofen Inhibitor COX Tyrphostin 25 Inhibitor EGFR Ropinirole hydrochloride Agonist DRD2 Ebselen Inhibitor Iproniazid phosphate Inhibitor MAO (B1)-p-Chlorophenylalanine Inhibitor Tryptophan hydroxylase Etazolate hydrochloride Inhibitor Phosphodiesterase Imetit dihydrobromide Agonist H3 Melatonin Agonist SKF 89976A hydrochloride Inhibitor GAT-1 Pimozide Antagonist DRD2 Resveratrol Inhibitor COX (−)-Physostigmine Inhibitor Cholinesterase Phenytoin sodium Metrifudil Agonist A2 Hydrochlorothiazide Inhibitor Carbonic anhydrase S-Methylisothiourea hemisulfate Inhibitor iNOS UK 14,304 Agonist alpha2 Adenosine Agonist Pheniramine maleate Antagonist HRH1 Hydroxytacrine maleate Inhibitor Cholinesterase Guanidinyl-naltrindole di-trifluoroacetate Antagonist kappa (+)-Bicuculline Antagonist GABA-A GR 125487 sulfamate salt Antagonist 5-HT4 Sulindac Inhibitor COX Chlorpropamide Releaser Insulin H-9 dihydrochloride Inhibitor cAMP- and cGMP-dependent PKs Nocodazole Inhibitor beta-tubulin Ciclosporin Inhibitor Calcineurin phosphatase Clodronic acid Inhibitor MMP1/collagenase Triamcinolone Agonist Glucocorticoid Alaproclate hydrochloride Inhibitor Reuptake U-75302 Agonist BLI1 O-Methylserotonin hydrochloride Agonist ARL 67156 trisodium salt Inhibitor ecto-ATPase GW5074 Inhibitor Raf1 kinase p-Iodoclonidine hydrochloride Agonist alpha2 1-[2-(Trifluoromethyl)phenyl]imidazole Inhibitor NOS L-Cycloserine Inhibitor Ketosphinganine synthetase Thioperamide maleate Antagonist H3 (B1)-Synephrine Agonist alpha Tyrphostin AG 528 Inhibitor EGFR Thiocitrulline Inhibitor nNOS, eNOS S-(−)-Lisuride Agonist DRD2 D-Serine Agonist NMDA-Glycine SKF 75670 hydrobromide Agonist D1 Fusaric acid Inhibitor Dopamine beta-hydroxylase Memantine hydrochloride Antagonist NMDA 2-Iodomelatonin Agonist Citicoline sodium Inhibitor PLA2 R-(−)-Fluoxetine hydrochloride Inhibitor Reuptake Y-27632 dihydrochloride Inhibitor ROCK 8-Cyclopentyl-1,3-dimethylxanthine Antagonist A1 Xamoterol hemifumarate Agonist beta1 L-655,240 Antagonist TXA2 Naftopidil dihydrochloride Antagonist alpha1 S(−)-IBZM Ligand DRD2 Flutamide Inhibitor Androgen Lidocaine hydrochloride Modulator (B1)-Chloro-APB hydrobromide Agonist D1 Arecoline hydrobromide Agonist S(−)-DS 121 hydrochloride Antagonist Autoreceptor (+)-MK-801 hydrogen maleate Antagonist NMDA Foliosidine Valproic acid sodium McN-A-343 Agonist M1 1,3-Dipropyl-7-methylxanthine Antagonist A2 Pindolol Antagonist beta DL-erythro-Dihydrosphingosine Inhibitor PKC/PLA2/PLD Ruthenium red Inhibitor Mitochondrial uniporter Disopyramide phosphate Modulator 8-Cyclopentyl-1,3-dipropylxanthine Antagonist A1 Betaine aldehyde chloride Metabolite Choline dehydrogenase Demeclocycline hydrochloride Protein synthesis Vancomycin hydrochloride from Streptomyces orientalis Cell wall synthesis Terazosin hydrochloride Antagonist alpha1 3-Iodo-L-tyrosine Inhibitor Tyrosine hydroxylase p-Aminoclonidine hydrochloride Agonist alpha2 gamma-D-Glutamylaminomethylsulfonic acid Antagonist Kainate SKF 89626 Agonist D1 Hydrocortisone 21-hemisuccinate sodium Cortisol Carbachol Agonist Lansoprazole Inhibitor H+ pump 4-Chloromercuribenzoic acid Inhibitor Nialamide Inhibitor MAO N-Ethylmaleimide Inhibitor Isocitrate dehydrogenase Mibefradil dihydrochloride Blocker T-type Methysergide maleate Antagonist Tetracaine hydrochloride Modulator 3-(1H-Imidazol-4-yl)propyl di(p-fluorophenyl)methyl ether Antagonist H3 hydrochloride Phenylbenzene-omega-phosphono-alpha-amino acid Antagonist R(+)-IAA-94 Inhibitor 1,4-Dideoxy-1,4-imino-D-arabinitol Inhibitor Glycogen phosphorylase 5-Fluoroindole-2-carboxylic acid Antagonist NMDA-Glycine MRS 1845 Inhibitor SOC S-(p-Azidophenacyl)glutathione Modulator Glutathione S-transferase Bretylium tosylate Blocker MRS 1523 Antagonist A3 Aminoguanidine hydrochloride Inhibitor NOS Xanthine amine congener Antagonist A1 Roscovitine Inhibitor CDK Acetyithiocholine chloride Agonist Nicotinic Na-p-Tosyl-L-lysine chloromethyl ketone hydrochloride Inhibitor Adenylyl cyclase Benserazide hydrochloride Inhibitor Decarboxylase 6-Nitroso-1,2-beazopyrone Inhibitor PARP GW1929 Agonist PPAR-gamma Ranitidine hydrochloride Antagonist H2 1,5-Isoquinolinediol Inhibitor PARS (+)-Bromocriptine methanesulfonate Agonist DRD2 R(+)-Butylindazone Inhibitor K+/Cl− transport 5-Hydroxy-L-tryptophan Precursor SB 228357 Antagonist 5-HT2B/2C DPMA Agonist A2 5-(N,N-hexamethylene)amiloride Inhibitor Na+/H+ Antiporter Estrone Estrogen YS-035 hydrochloride Blocker L-type (−)-Nicotine hydrogen tartrate salt Agonist Nicotinic Diazoxide Activator ATP-sensitive LY-310,762 hydrochloride Antagonist 5-HT1D Fenoldopam bromide Agonist D1 MHPG piperazine Metabolite Famotidine Antagonist H2 Milrinone Inhibitor PDE III Methyl beta-carboline-3-carboxylate Agonist Oxaprozin Inhibitor Nalbuphine hydrochloride Antagonist Cyclobenzaprine hydrochloride Antagonist 5-HT2 T-0156 Inhibitor PDE V Chlorambucil Intercalator L-Methionine sulfoximine Inhibitor Glutamine synthase PD 404,182 Inhibitor KDO-8-P synthase 3-Methyl-6-(3-[trifluoromethyl]phenyl)-1,2,4-triazolo[4,3- Agonist BZ1 b]pyridazine 6-Methyl-2-(phenylethynyl)pyridine hydrochloride Antagonist mGluR5 (B1)-Norepinephrine (+)bitartrate Agonist GR 4661 Agonist 5-HT1D S-(4-Nitrobenzyl)-6-thioguanosine Inhibitor Azelaic acid Inhibitor Metrazoline oxalate Ligand Nilutamide Inhibitor Androgen Spiroxatrine Agonist 5-HT1A Desipramine hydrochloride Inhibitor Uptake Tetraethylammonium chloride Antagonist Nicotinic 6,7-Dichloroquinoxaline-2,3-dione Antagonist NMDA-glycine DL-p-Chlorophenylalanine methyl ester hydrochloride Inhibitor Tryptophan hydroxylase Fluvoxamine maleate Inhibitor Reuptake NBI 27914 Antagonist CRF1 Lomefloxacin hydrochloride Inhibitor DNA Gyrase NG-Nitro-L-arginine Inhibitor NOS 1,10-Diaminodecane Agonist NMDA-polyamine (inverse) Allopurinol Inhibitor Xanthine oxidase AIDA Antagonist mGluR1 (B1)-cis-Piperidine-2,3-dicarboxylic acid Agonist NMDA Propentofylline Inhibitor Transporter Urapidil hydrochloride Antagonist alpha1 L-Aspartic acid Agonist Pentolinium di[L(+)-tartrate] Antagonist Nicotinic Tomoxetine Inhibitor Reuptake (−)-cis-(1S,2R)-U-50488 tartrate Ligand Sigma receptor Tranilast Inhibitor LTC4 Cilostamide Inhibitor PDE III Tyrphostin 47 Inhibitor EGFR CGS-15943 Antagonist A1 Muscimol hydrobromide Agonist GABA-A, GABA-C 4-Androsten-4-ol-3,17-dione Inhibitor Aromatase Palmitoyl-DL-Carnitine chloride Modulator PKC Fiduxosin hydrochloride Antagonist alpha1 Dihydroouabain Inhibitor Na+/K+ Pump Quazinone Inhibitor PDE III (S)-ENBA Agonist A1 Moxonidine hydrochloride Agonist alpha2A L-Tryptophan Precursor Pirenperone Antagonist 5-HT2 1-(1-Naphthyl)piperazine hydrochloride Antagonist 5-HT2 Pyridostigmine bromide Inhibitor Cholinesterase 5-hydroxydecanoic acid sodium Blocker Isoxanthopterin Metabolite Thioridazine hydrochloride Antagonist D1/D2 (−)-Isoproterenol hydrochloride Agonist beta Dilazep hydrochloride Inhibitor Uptake SKF 94836 Inhibitor PDE III Bromoenol lactone Inhibitor PLA2 RX 821002 hydrochloride Antagonist alpha2 Phthalamoyl-L-glutamic acid trisodium Agonist NMDA Piroxicam Inhibitor COX (B1)-Pindobind Ligand beta Hydralazine hydrochloride Inhibitor MAO-A/B p-MPPI hydrochloride Antagonist 5-HT1A Benoxathian hydrochloride Antagonist alpha1 Lidocaine N-ethyl bromide quaternary salt Antagonist Beclomethasone Glucocorticoid Bupropion hydrochloride Blocker Reuptake SU 4312 Inhibitor KDR Hypotaurine Inhibitor Antioxidant L-3,4-Dihydroxyphenylalanine methyl ester hydrochloride Precursor ATPA Agonist Kainate L-368,899 Antagonist Oxytocin receptor Xylometazoline hydrochloride Agonist alpha Diclofenac sodium Inhibitor COX NADPH tetrasodium Cofactor Rottlerin Inhibitor PKC/CaM Kinase III L-165,041 Agonist PPAR-gamma 1-Methylbistamine dihydrochloride Metabolite BRL 15572 Antagonist 5-HT1D trans-(B1)-ACPD Agonist Metabotropic HA-1004 hydrochloride Inhibitor PK SU 6656 Inhibitor Src family kinase Dobutamine hydrochloride Agonist beta1 Caffeic Acid Inhibitor Antioxidant (B1)-CPP Antagonist NMDA MDL 26,630 trihydrochloride Agonist NMDA-Polyamine 4-DAMP methiodide Antagonist M3 Sandoz 58-035 Inhibitor ACAT Tyrphostin AG 112 Inhibitor Tyrosine kinase 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride Inhibitor PKA/PKC N-p-Tosyl-L-phenylalanine chloromethyl ketone Inhibitor Chymotrypsin alpha BRL 54443 maleate Agonist 5-HT1E/1F (B1)-alpha-Lipoic Acid Coenzyme Pyruvate dehydrogenase Ro 04-6790 dihydrochloride Antagonist 5-HT6 (B1)-Propranolol hydrochloride Antagonist beta 6,7-ADTN hydrobromide Agonist Amifostine Inhibitor Cytoprotectant SCH-202676 hydrobromide Modulator GPCR THIP hydrochloride Agonist GABA-A A-315456 Antagonist alpha1D 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride Inhibitor Serine Protease Furegrelate sodium Inhibitor Thromboxane synthase Thio-NADP sodium Blocker NAADP-induced Theophylline Antagonist A1 > A2 alpha-Methyl-DL-tyrosine methyl ester hydrochloride Inhibitor Tyrosine hydroxylase Xylazine hydrochloride Agonist alpha2 6-Hydroxymelatonin Metabolite Propofol Inhibitor Muscarinic 5-fluoro-5′-deoxyuridine Inhibitor Ibudilast Inhibitor PDE IV Telenzepine dihydrochloride Antagonist M1 N-(2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl)-3-methoxybenzamide Agonist D4 N-arachidonylglycine Inhibitor FAAH nor-Binaltorphimine dihydrochloride Antagonist kappa Naltrexone hydrochloride Antagonist Spermine tetrahydrochloride Antagonist NMDA-Polyamine Flunarizine dihydrochloride Blocker Na+/Ca2+ channel BU224 hydrochloride Antagonist I2 Pancuronium bromide Antagonist Ergocristine Agonist Wortmannin from Penicillium funiculosum Inhibitor PI3K Caffeine Inhibitor Phosphodiesterase Se-(methyl)selenocysteine hydrochloride Inhibitor Cirazoline hydrochloride Agonist alpha1A SKY 95282 dimaleate Antagonist H2 Progesterone Progesterone Hydroquinone Inhibitor . Vinpocetine Inhibitor PDE I YC-1 Activator Guanylyl cyclase Lonidamine Inhibitor Mitochondrial hexokinase (+)-Quisqualic acid Agonist AMPA Minocycline hydrochloride Inhibitor 3-alpha,21-Dihydroxy-5-alpha-pregnan-20-one Modulator GABA-A L-701,324 Antagonist NMDA-Glycine Orphenadrine hydrochloride Antagonist Muscarinic Imazodan Inhibitor PDE II N-Oleoyldopamine Ligand CB1 N-Acetyldopamine monohydrate Precursor Promethazine hydrochloride Antagonist HRH1 1-(5-Isoquinolinylsulfonyl)-3-methylpiperazine dihydrochloride Inhibitor PKC Antozoline hydrochloride Agonist Amfonelic acid Modulator 9-cyclopentyladenine Inhibitor Adenylate cyclase Chloroquine diphosphate Intercalator DNA L-732,138 Antagonist NK1 > NK2, NK3 (+)-Catechin Hydrate Inhibitor Antioxidant L-Buthionine-sulfoximine Inhibitor (B1)-Thalidomide Inhibitor TNFalpha 1-Aminobenzotriazole Inhibitor CYP450, chloroperoxidase Rilmenidine hemifumarate Agonist I1 N6-2-Phenylethyladenosine Agonist A1 Taurine Agonist Diltiazem hydrochloride Antagonist L-type CR 2945 Antagonist CCK-B O-Phospho-L-serine Antagonist NMDA Clozapine Antagonist D4 > D2, D3 Beuzamide Inhibitor PARS alpha-Lobeline hydrochloride Agonist Nicotinic Procaine hydrochloride Blocker L-Arginine Precursor SQ 22536 Inhibitor Adenylyl cyclase K 185 Antagonist Trimipramine maleate Inhibitor Reuptake Aurintricarboxylic acid Inhibitor TopoII 2-Methyl-5-hydroxytryptamine maleate Agonist 5-HT3 2-Phenylaminoadenosine Agonist A2 > A1 VUF 5574 Antagonist A3 Me-3,4-dephostatin Inhibitor PP1B/SHPTP-1 Ketoconazole Inhibitor Cytochrome P450c17 Ro 20-1724 Inhibitor cAMP phosphodiesterase Agmatine sulfate Agonist Sulindac sulfone Inhibitor Oxatomide Modulator Piceatannol Inhibitor Syk/Lck (−)-3-Methoxynaltrexone hydrochloride Antagonist (−)-Naproxen sodium Inhibitor COX (+)-Cyclazocine Antagonist S(−)-Atenolol Antagonist beta1 Primidone Dephostatin Inhibitor CD45 Tyrosine Kinase CL 316, 243 Agonist beta3 Cephapirin sodium Cell wall synthesis JWH-015 Agonist CB2 Methapyrilene hydrochloride Antagonist HRH1 (−)-Eseroline fumarate Inhibitor Cholinesterase DL-Stearoylcarnitine chloride Inhibitor PKC Terbutaline hemisulfate Agonist beta Bestatin hydrochloride Inhibitor Aminopeptidase Droperidol Antagonist D1/D2 (−)-Scopolamine,n-Butyl-, bromide Antagonist Muscarinic CGP 20712A methanesulfonate Antagonist beta1 Procainamide hydrochloride Antagonist N-omega-Methyl-5-hydroxytryptamine oxalate salt Ligand (B1)-8-Hydroxy-DPAT hydrobromide Agonist 5-HT1A Nomifensine maleate Inhibitor Reuptake 6(5H)-Phenanthridinone Inhibitor PARP H-7 dihydrochloride Inhibitor PKC IEM-1460 Inhibitor AMPA Rutaecarpine Blocker Tiapride hydrochloride Antagonist D2/D3 S-Nitrosoglutathione Donor N-Methyl-beta-carboline-3-carboxamide Antagonist GABA-A Kynurenic acid Antagonist NMDA-Glycine AGN 192403 hydrochloride Ligand I1 Amitriptyline hydrochloride Inhibitor Uptake Uridine 5′-diphosphate sodium Agonist P2Y Oxybutynin Chloride Antagonist Muscarinic U0126 Inhibitor MEK1/MEK2 Cephradine Cell wall synthesis N-Succinyl-L-proline Inhibitor ACE BW 723C86 Agonist 5-HT2B Chelidamic acid Inhibitor L-glutamic decarboxylase (B1)-alpha-Methyl-4-carboxyphenylglycine Antagonist Metabotropic N6-Phenyladenosine Agonist A1 N6-Methyladenosine Agonist DL-Homatropine hydrobromide Antagonist Muscarinic Sodium Oxamate Inhibitor Lactate Dehydrogenase ZM 39923 hydrochloride Inhibitor JNK-3 Chlorpromazine hydrochloride Antagonist 1,3-Dimethyl-8-phenylxanthine Antagonist A1 Terfenadine Antagonist HRH1 Protriptyline hydrochloride Blocker Reuptake AB-MECA Agonist A3 1-(4-Hydroxybenzyl)imidazole-2-thiol Inhibitor Dopamine beta-hydroxylase 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole Agonist ER-alpha 2,4-Dinitrophenyl 2-fluoro-2-deoxy-beta-D-glucopyranoside Inhibitor exo-beta-(1,3)-Glucanase Picrotoxin Antagonist GABA-C FSCPX Antagonist A1 Hemicholinium-3 Blocker Uptake SKY 83565 hydrobromide Agonist D1 Phenylbutazone Substrate Prostaglandin peroxidase L-162,313 Agonist AT1 SB 205384 Modulator GABA-A Dantrolene sodium Inhibitor Release DCEBIO Activator hlK1 Paromomycin sulfate Protein synthesis Cilostazol Inhibitor PDE III Tropicamide Antagonist M4 L-Glutamine Agonist Nisoxetine hydrochloride Blocker Reuptake BTCP hydrochloride Blocker Reuptake Diphenhydramine hydrochloride Antagonist HRH1 (B1)-Bay K 8644 Agonist L-type Oxotremorine sesquifumarate salt Agonist M2 Chloroethylclonidine dihydrochloride Antagonist alpha1B 4-Diphenylacetoxy-N-(2-chloroethyl)piperidine hydrochloride Antagonist Muscarinic TPMPA Antagonist GABA-C Betamethasone Glucocorticoid SKF 86466 Antagonist alpha2 Gabapentin Hispidin Inhibitor PKC-beta 5,7-Dichlorokynurenic acid Antagonist NMDA-glycine PD 98,059 Inhibitor MEK2 Farnesylthiosalicylic acid Antagonist Ras Phloretin Blocker L-Type Oxolinic acid Inhibitor DNA Gyrase MRS 1754 Antagonist A2B Guanfacine hydrochloride Agonist alpha2 Amiodarone hydrochloride Agonist alpha/beta DNQX Antagonist Kainate/quisqualate 4-Phenyl-3-furoxancarbonitrile Donor 5alpha-Pregnan-3alpha-ol-20-one Modulator GABA-A SB 203186 Antagonist 5-HT4 1-(3-Chlorophenyl)piperazine dihydrochlonde Agonist 5-HT1 U-83836 dihydrochloride Inhibitor Ketotifen fumarate Antagonist HRH1 Phaclofen Antagonist GABA-B Mianserin hydrochloride Antagonist (6R)-5,6,7,8-Tetrahydro-L-biopterin hydrochloride Cofactor Tyrosine Quipazine, 6-nitro-, maleate Inhibitor Reuptake L-azetidine-2-carboxylic acid Inhibitor Collagen Betaxolol hydrochloride Antagonist beta1 D(−)-2-Amino-7-phosphonoheptanoic acid Antagonist NMDA Pyrilamine maleate Antagonist HRH1 GR 113808 Antagonist 5-HT4 (B1)-Verapamil hydrochloride Modulator L-type N-Acetyltryptamine Agonist- Antagonist Furafylline Inhibitor P450IA2 4-Hydroxyphenethylamine hydrochloride Agonist BW 245C Agonist DP Clonidine hydrochloride Agonist alpha2 4-Methylpyrazole hydrochloride Inhibitor Alcohol dehydrogenase 8-(p-Sulfophenyl)theophylline Antagonist A1 > A2 ICI 118,551 hydrochloride Antagonist beta2 PPADS Antagonist P2 Acetazolamide Inhibitor Carbonic anhydrase SC-560 Inhibitor COX-1 Carbamazepine NF 023 Antagonist P2X1 Hydroxyurea Inhibitor Ribonucleoside reductase (−)-MK-801 hydrogen maleate Antagonist NMDA 2-Chloroadenosine triphosphate tetrasodium Agonist P2Y (B1)-HA-966 Antagonist NMDA-glycine (B1)-PD 128,907 hydrochloride Agonist D3 BU99006 Ligand I2 Rp-cAMPS triethylamine Inhibitor PKA (−)-alpha-Methylnorepinephrine Agonist 6-Hydroxy-DL-DOPA Neurotoxin 1-Phenyl-3-(2-thiazolyl)-2-thiourea Inhibitor beta-Hydroxylase Trihexyphenidyl hydrochloride Antagonist Muscarinic 8-(4-Chlorophenylthio)-cAMP sodium Activator Neostigmine bromide Inhibitor Acetylcholinesterase Cyproheptadine hydrochloride Antagonist 5-HT2 (2S,1$$S,2$$S)-2-(carboxycyclopropyl)glycine Agonist mGluR2 3-Aminopropionitrile fumarate Substrate CYP450 7-Chlorokynurenic acid Antagonist NMDA 1-Deoxynojirimycin hydrochloride Inhibitor alpha-glucosidase Atropine sulfate Antagonist Muscarinic Tryptamine hydrochloride Ligand (B1)-2-Amino-3-phosphonopropionic acid Antagonist NMDA S(−)-Willardiine Agonist AMPA/kainate U-99194A maleate Antagonist D3 Spermidine trihydrochloride Ligand NMDA-Polyamine Capsazepine Agonist (B1)-SKF-38393 hydrochloride Antagonist D1 gamma-Acetylinic GABA Inhibitor GABA transaminase Atropine methyl nitrate Antagonist Muscarinic Caffeic acid phenethyl ester Inhibitor NFkB PRE-084 Agonist sigma1 (B1)-Taxifolin Inhibitor Antioxidant Ro 41-1049 hydrochloride Inhibitor MAO-A Dihydrokainic acid Blocker Kainate Dopamine hydrochloride Agonist SB 218795 Antagonist NK3 MJ33 Inhibitor PLA2 R(+)-SCH-23390 hydrochloride Antagonist D1 5,5-Diphenylhydantoin CP55940 Agonist Sphingosine Inhibitor PKC Dicyclomine hydrochloride Antagonist Muscarinic Tolazamide Releaser Insulin A-77636 hydrochloride Agonist D1 Bromoacetyl alprenolol menthane Antagonist beta 3,7-Dimethyl-I-propargylxanthine Antagonist A2 2,2$$-Bipyridyl Inhibitor Metalloprotease L-Cysteinesulfinic Acid Ligand (B1)-Octoclothepin maleate Antagonist DRD2 GW9662 Inhibitor PPAR-gamma Phenamil methanesulfonate Inhibitor Amiloride sensitive Ethylene glycol-bis(2-aminoethylether)-N,N,N$$,N$$-tetraacetic acid Inhibitor Carboxypeptidase B Ivermectin Modulator alpha7 nACh Prilocaine hydrochloride Blocker Benzamidine hydrochloride Inhibitor Peptidase Tyrphostin AG 698 Inhibitor EGFR AA-861 Inhibitor 5-lipoxygenase DSP-4 hydrochloride Neurotoxin Clorgyline hydrochloride Inhibitor MAO-A Cisplatin Intercalator R(+)-6-Bromo-APB hydrobromide Agonist D1/D5 Olomoucine Inhibitor PK Molsidomine Donor Dextrorphan D-tartrate Antagonist NMDA Astaxanthin Inhibitor Antioxidant Fluspirilene Antagonist D2/D1 R(−)-SCH-12679 maleate Antagonist D1 Hydroxylamine hydrochloride Inhibitor MAO Mizoribine Inhibitor IMP dehydrogenase Icilin Agonist CMR1 Cimetidine Antagonist H2 5-Carboxamidotryptamine maleate Agonist 5-HT7 Risperidone Antagonist DRD2 TMB-8 hydrochloride Antagonist Picotamide Antagonist TXA2 Doxylamine succinate Antagonist HRH1 3-deazaadenosine Inhibitor 1-(m-Chlorophenyl)-biguanide hydrochloride Agonist 5-HT3 Sepiapterin Cofactor NOS Tyrphostin AG 490 Inhibitor JAK2 Apigenin Inhibitor NF449 octasodium salt Antagonist Gs-alpha Methiothepin mesylate Antagonist 5-HT1E, 5-HT1F, 5-HT6 Nicardipine hydrochloride Antagonist L-type Tyrphostin AG 1478 Inhibitor EGFR 5-(N-Methyl-N-isobutyl)amiloride Blocker Na+/H+ Antiporter 4-Amino-1,8-naphthalimide Inhibitor PARP Furosemide Inhibitor Na+, K+, Cl− cotransport (B1)-2-Amino-4-phosphonobutyric acid Antagonist NMDA S(+)-Raclopride L-tartrate Antagonist DRD2 Methylcarbamylcholine chloride Agonist Nicotinic Naloxone benzoylhydrazone Agonist kappa N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide Ligand Mitochondria Androsterone Androgen Reactive Blue 2 Antagonist P2Y 1,3-Diethyl-8-phenylxanthine Antagonist A1 Fusidic acid sodium Inhibitor SCH-28080 Inhibitor H+/K+-ATPase Danazol Inhibitor Calcimycin Ca2+ Bay 11-7085 Inhibitor IkB-alpha Carmustine Intercalator 1,3-PBIT dihydrobromide Inhibitor NOS Ceftriaxone sodium Cell wall synthesis Tyrphostin AG 835 Inhibitor Tyrosine kinase Cystamine dihydrochloride Inhibitor Transglutaminase Meclofenamic acid sodium Inhibitor COX/5-Lipoxygenase Cephalothin sodium Cell wall synthesis Suramin hexasodium Antagonist P2X, P2Y 8-Bromo-cAMP sodium Activator Tetraethylthiuram disulfide Inhibitor Alcohol Dehydrogenase WIN 62,577 Antagonist NK1 5-(N,N-Dimethyl)amiloride hydrochloride Blocker Na+/H+ Antiporter Sodium nitroprusside dihydrate Releaser SB 200646 hydrochloride Antagonist 5-HT2C/2B L-3,4-Dihydroxyphenylalanine Precursor Cefmetazole sodium Cell wall synthesis MDL 105,519 Antagonist NMDA-Glycine 5-Bromo-2$$-deoxyuridine Inhibitor Nordihydroguaiaretic acid from Larrea divaricata (creosote bush) Inhibitor Lipoxygenase Tetramisole hydrochloride Inhibitor Phosphatase Pregnenolone sulfate sodium Antagonist GABA-A Clemizole hydrochloride Antagonist HRH1 NCS-356 Agonist gamma-Hydroxybutyrate (Z)-Gugglesterone Antagonist FRX R(+)-Atenolol Antagonist beta1 Leflunomide Inhibitor LFM-A13 Inhibitor BTK 1,3-Dipropyl-8-p-sulfophenylxanthine Antagonist A1 > A2

TABLE 4 Total active Class in class^(†) Total in class % Active in class Adenosine 4 56 7.1 Adrenceptor 5 103 4.9 Antibiotics 8 29 27.6 Anticonvulsant 1 12 8.3 Apoptosis 6 11 54.5 Biochemistry 6 46 13.0 Calcium Channels 2 26 7.7 Cannabinoid 1 6 16.7 Cell Cycle 5 15 33.3 Cell Stress 3 20 15.0 Cholinergic 8 77 10.4 Cyclic Neucleotides 4 31 12.9 Cytoskeleton and ECM 6 10 60.0 DNA 10 29 34.5 Dopamine 22 113 19.5 GABA 2 41 4.9 Glutamate 9 88 10.2 Histamine 2 32 6.3 Hormone 3 33 9.1 Imidazoline 1 11 9.1 Immune System 1 11 9.1 Intracellular Calcium 2 7 28.6 Ion Pump 3 16 18.8 K+ Channel 1 17 5.9 Lipid 1 9 11.1 Na+ Channel 3 17 17.6 Neurotransmission 4 45 8.9 Nitric Oxide 5 37 13.5 Opioid 6 27 22.2 P2 Receptor 2 14 14.3 Phosphorylation 9 93 9.7 Prostaglandin 1 24 4.2 Serotonin 12 83 14.5 Vanilloid 2 5 40.0 Screen Total 160 1267 12.6^(‡) Screen Total 2^(§) 122 1154 10.6 ^(†)Only includes inhibitors of MTT readings. ^(‡)Frequency of whole screen ^(§)Total calculated without cytotoxic compounds: antibiotics, apoptosis, cell cycle, cell stress, cytoskeleton, and DNA

TABLE 5 HTS Bioactive Pharmacological Classes EC50% EC50% Neurosphere Astrocyte Neurosphere Name Action Target Selectivity (μm) (μm) Specificity Negative Control Cycloheximide Inhibitor Protein Synthesis 60S Ribosome 0.142 0.0711 0.502 Etoposide Inhibitor Topoisomerase Topo II 0.340 0.433 1.28 Carboplatin Intercalator DNA — 0.489 2.453 5.08 Dopamine Perphenazine Antagonist Dopamine Receptor D2 23.12 n.d. >4 (±)-Butaclamol Antagonist Dopamine D2 > D1 0.785 12.34 15.7 hydrochloride R(−)-Propylnorapomorphine Agonist Dopamine D2 0.3512 8.23 23.4 hydrochloride Apomorphine hydrochloride Agonist Dopamine — 0.3499 10.19 29.1 hemihydrate cis-(Z)-Flupenthixol Antagonist Dopamine — 0.1993 1.182 5.93 dihydrochloride Receptor Ion Channels Bepridil hydrochloride Blocker Ca2+ Channel — 2.70 4.724 1.75 Dequalinium dichloride Blocker K+ channels Apamin- 1.474 1.418 0.962 sensitive Muscarinic Hexahydro-sila-difenidol Antagonist Acetylcholine Receptor M3 > M1 > M2 0.441 5.815 13.2 hydrochloride Methoctramine Antagonist Acetylcholine Receptor M2 1.053 0.0845 0.802 tetrahydrochloride NMDA Ifenprodil tartrate Blocker NMDA Polyamine site 0.616 11.06 17.9 Pentamidine isethionate Antagonist NMDA Receptor — 0.822 1.995 2.43 Nitric Oxide Diphenyleneiodonium Inhibitor Nitric Oxide Synthase eNOS 0.011 0.0209 1.88 chloride 7-Nitroindazole Inhibitor Nitric Oxide Synthase nNOS 76.3 282.6 3.71 Opioid Metaphit methanesulfonate Antagonist Opioid sigma 10.0 3.624 0.361 Carbetapentane citrate Ligand Opioid sigma 1 0.756 28.16 37.3 Phosphorylation Chelerythrine chloride Inhibitor PKC — 0.396 1.531 3.87 Retinoic acid p- Vitamin A RAR — 0.334 2.399 7.18 hydroxyanilide acid analog WHI-P131 Inhibitor JAK3 — 2.346 — >10 SB 202190 Inhibitor p38 MAPK — 8.063 64.8 8.04 Serotonin Methiothepin mesylate Antagonist Serotonin 5-HT1E/F, 5- 2.663 3.698 1.39 HT6 Metergoline Antagonist Serotonin 5-HT2/ 1.624 3.285 2.02 5-HT1D PAPP Agonist Serotonin 5-HT1A 0.031 21.82 702 CGS-12066A maleate Agonist Serotonin 5-HT1B 2.007 14.4 7.17 Vanilloid Dihydrocapsaicin Agonist Vanilloid Receptor VR1 0.218 41.83 192

TABLE 6 Effect of Normal Neural Precursor Specific Agents on Medulloblastoma Derived Neurospheres Medulloblastoma Name Action Target Selectivity Neurosphere EC₅₀ (μM) Controls Cycloheximide Inhibitor Protein Synthesis 60S Ribosome 0.042 Etoposide Inhibitor Topoisomerase Topo II 0.208 Carboplatin Intercalator DNA — 0.196 Selected Hits^(†) (±)Butaclamol Antagonist Dopamine Receptor D2 > D1 0.751 R(−) Propylnorapomorphine Agonist Dopamine Receptor D2 0.199 Apomorphine Agonist Dopamine Receptor — 0.168 cis-(Z) Flupenthixol Antagonist Dopamine Receptor — 0.187 Hexahydro-sila-difenidol Antagonist Acetylcholine Receptor M3 > M1 > M2 1.125 Ifenprodil tartrate Antagonist NMDA Receptor Polyamine site 0.451 Carbetapentane citrate Agonist Opioid Receptor sigma 1 2.083 Fenretinide Agonist Retinoic Acid Receptor — 0.204 WHI-P131 Antagonist JAK3 — 1.525 SB 202190 Antagonist p38 MAPK — 3.006 PAPP Agonist Serotonin Receptor 5-HT1A 0.169 Dihydrocapsaicin Agonist Vanilloid Receptor VR1 0.020

TABLE 7 Standard incidence ratios (SIR) of brain tumors in cohorts previously diagnosed with a variety of mental disorders (only studies published after 2000 were used). “Reported SIR” “Revised SIR” Study Year Disease (95% CI) (95% CI)^(†) Lichtermann et al.¹¹ 2001 Schizophrenia 0.88 (0.62-1.20) 0.88 (0.62-1.20) Dalton et al.¹⁶ 2002 Bipolar psychosis 0.82 (0.53-1.20) 0.64 (0.31-1.17)^(†) Dalton et al.¹⁶ 2002 Unipolar psychosis 1.19 (0.99-1.43) 0.99 (0.70-1.34)^(†) Dalton et al.¹⁶ 2002 Reactive Depression 1.20 (0.92-1.55) 0.73 (0.42-1.18)^(†) Dalton et al.¹⁶ 2002 Dysthymia 1.34 (1.05-1.68) 0.82 (0.52-1.23)^(†) Lalonde et al.¹⁰ 2003 Parkinson's 0.20 (0.17-0.23) 0.20 (0.17-0.23) Carney et al.¹⁸ 2004 Any mental (Male) 2.09 (1.22-3.59) — Carney et al.¹⁸ 2004 Any mental (Female) 2.12 (1.40-3.21) — Goldacre et al.¹³ 2005 Schizophrenia 0.74 (0.29-1.53) 0.74 (0.29-1.53) Olsen et al.¹⁷ 2005 Parkinson's 1.32 (0.90-1.90) 0.85 (0.31-2.34)^(†) Grinshpoon et al.¹⁵ 2005 Schizophrenia (Male) 0.56 (0.32-0.81) 0.56 (0.32-0.81) Grinshpoon et al.¹⁵ 2005 Schizophrenia (Female) 0.94 (0.62-1.27) 0.94 (0.62-1.27) Barak et al.¹⁴ 2005 Schizophrenia 0.20 (0.00-1.09) 0.20 (0.00-1.09) Dalton et al.¹² 2005 Schizophrenia (Male) 0.74 (0.42-1.20) 0.74 (0.42-1.20) Dalton et al.¹² 2005 Schizophrenia (Female) 0.78 (0.44-1.26) 0.78 (0.44-1.26) Diamandis 2007 Combined 1.15

(1.01-1.30)* 0.80

(0.67-0.95)** ^(†)Qualifying brain cancer cases have been modified as noted by authors to only include cases more than 2 years after mental disorder diagnosis.

Excludes data from Lalonde et al (2003). Although supportive, the large sample size in this study would significantly skew the results of the analysis.

Excludes data from Carney et al (2004) as authors did not reanalyze their data following the observed temporal discrepancy in their brain tumor SIR. *p = 0.04; **p = 0.01 ¹⁰Lalonde, F. M. & Myslobodsky, M. Breast 12, 280-282 (2003). ¹¹Lichtermann, D., Arch. Gen. Psychiatry 58, 573-578 (2001). ¹²Dalton, S. O., et al, Schizophr. Res. 75, 315-324 (2005). ¹³Goldacre, M. J., et al Br. J. Psychiatry 187, 334-338 (2005). ¹⁴Barak, Y., et al., Cancer 104, 2817-2821 (2005). ¹⁵Grinshpoon, A. et al. 73, 333-341 (2005). ¹⁶Dalton, S. O., et al. Am. J. Epidemiol. 155, 1088-1095 (2002). ¹⁷Olsen, J. H. et al. 92, 201-205 (2005). ¹⁸Carney, C. P., et al Psychosom. Med. 66, 735-743 (2004).

TABLE 8 Assessment of the potency and selectivity of a subset of the identified bioactive agents Neurosphere Astrocyte Neurosphere Name Action Target Selectivity EC₅₀ (μM) EC₅₀(μM) Selectivity Controls Cycloheximide (1) Inhibitor Protein Synthesis 60S Ribosome 0.142 0.071 0.50 Etoposide (2) Inhibitor Topoisomerase Topo II 0.340 0.433 1.28 Carboplatin (3) Intercalator DNA — 0.489 2.453 5.08 Sobuzaxane (19) Inhibitor Topoisomerase Topo II 10.19 n.t. n/a Mevastatin (20) Inhibitor n/a Ras, Rho 0.142 n.t. n/a Taxol (21) Inhibitor Tubulin — 0.010 n.t. n/a Vinblastine(22) Inhibitor Tubulin — 0.028 n.t. n/a Vincristine (23) Inhibitor Tubulin — >0.001 n.t. n/a Adrenergic R(−)-Denopamine (24) Agonist Adrenoceptor Beta 1 39.2 n.t. n/a Rauwolscine (25) Antagonist Adrenoceptor Alpha 2 66.37 n.d. >1.43 Dopamine Perphenazine (26) Antagonist Dopamine Receptor D2 23.12 n.d. >4 (±)-Butaclamol (4) Antagonist Dopamine D2 > D1 0.785 12.34 15.7 R(−)-Propylnorapomorphine (5) Agonist Dopamine D2 0.3512 8.23 23.4 R(−)-Apomorphine (6) Agonist Dopamine — 0.3499 10.19 29.1 cis-(Z)-Flupenthixol (7) Antagonist Dopamine Receptor — 0.1993 1.182 5.93 (+)-Bromocripline (18) Agonist Dopamine Receptor D2 1.187 n.t. n/a Cannaboid Indomethacin (27) Agonist Cannabinoid receptor CB2 n.d. n.t. n/a Ion Channels Bepridil (28) Blocker Ca2+ Channel — 2.70 4.724 1.75 Dequalinium (29) Blocker K+ channels Apamin-sensitive 1.474 1.418 0.962 MAO Quinacrine (30) Inhibitor MAO-A/B — 0.936 n.t. n/a Muscarinic p-F-HHSID (8) Antagonist Acetylcholine Receptor M3 > M1 > M2 0.441 5.815 13.2 Methoctramine (31) Antagonist Acetylcholine Receptor M2 1.053 0.0845 0.802 NMDA Ifenprodil (9) Blocker NMDA Polyamine site 0.616 11.06 17.9 Pentamidine (32) Antagonist NMDA Receptor — 0.822 1.995 2.43 Nitric Oxide Diphenyleneiodonium (33) Inhibitor Nitric Oxide Synthase eNOS 0.011 0.0209 1.88 7-Nitroindazole (34) Inhibitor Nitric Oxide Synthase nNOS 76.3 282.6 3.71 Opioid Metaphit (35) Antagonist Opioid sigma 10.04 3.624 0.361 Carbetapentane (10) Ligand Opioid sigma 1 0.756 28.16 37.3 Phosphorylation Chelerythrine (36) Inhibitor PKC — 0.396 1.531 3.87 Fenretinide (11) Vitamin A RAR — 0.334 2.399 7.18 acid analog WHI-P131 (12) Inhibitor JAK3 — 2.346 — >10 SB 202190 (13) Inhibitor p38 MAPK — 8.063 64.8 8.04 Tyrphoslin AG 34 (37) inhibitor Tyrosine Kinase — 9.917 n.t. n/a Serotonin Methiothepin (38) Antagonist Serotonin 5-HT1E/F, 5-HT6 2.663 3.698 1.39 Metergoline (39) Antagonist Serotonin 5-HT2/5-HT1D 1.624 3.285 2.02 PAPP (14) Agonist Serotonin 5-HT1A 0.031 21.82 702 CGS-12066A (40) Agonist Serotonin 5-HT1B 2.007 14.4 7.17 Vanilloid Dihydrocapsaicin (15) Agonist Vanilloid Receptor VR1 0.218 41.83 192 Other 5-Bromo-2′-deoxyuridine (41) Inhibitor DNA — 2.045 n.t. n/a 7,7-Dimethyl-(5Z,8Z)-eicosadienoic Inhibitor Phospholipase A_(z)/ — 5.170 n.t. n/a acid (42) Lipoxygenase n.d. = not determined at highest tested dose (30-95 μM) n.t. = not tested

TABLE 9 Normal and cancerous human neural precursor cells show sensitivity to a myriad of neurotransmission modulators hFetal hGBM1 hGBM2 precursors precursors precursors Name Action Target Selectivity EC₅₀ (μM)^(¶) EC₅₀ (μM)^(≠) EC₅₀ (μM)^(§) Controls Etoposide Inhibitor Topoisomerase Topo II 0.16 0.62 0.27 Carboplatin Intercalator DNA — 0.43 2.04 3.30 Selected Hits^(†) Apomorphine Agonist Dopamine Receptor — 5.26 14.58 0.31 p-F-HHSID Antagonist Acetylcholine Receptor M3 > M1 > M2 10.58 12.63 1.23 Ifenprodil Antagonist NMDA Receptor Polyamine site 0.42 1.99 0.206 Carbetapentane Agonist Opioid Receptor sigma 1 6.12 5.44 1.73 PAPP Agonist Serotonin Receptor 5-HT1A 0.22 1.87 0.31 Dihydrocapsaicin Agonist Vanilloid Receptor VR1 3.28 88.63 21.46 ^(†)Only a selected array of the identified mouse neural precursor selective agents were tested in human cells. All agents tested are displayed in this table. ^(¶)Values against neural precursors derived from human fetal CNS tissue. ^(≠)Pathological diagnosis of hGBM1 was WHO grade IV GMB ^(§)Pathological diagnosis of hGBM2 was WHO grade IV GBM (giant cell variant).

TABLE 10 Product Name Z score p value Activity Class Action Selectivity Likelihood score Cluster ID

−0.303 3.8107E−01 no Opioid Agonist kappa 1.9970 32 (−)

-(1S,2R)-

−2.833 2.3049E−03 yes Opioid Agonist kappa 7.8140 32 (±)

-(1S,2R)-U-504BB

0.171 4.3205E−01 no Neurotransmission Ligand Sigma receptor 0.0720 32 (−)-trans-(1R,2R)-U-50BB hydrochloride −0.207 3.0121E−01 no Opioid Agonist kappa 7.5748 32 (−)-trans-(1R,2R)-U-50BB hydrochloride −0.473 3.1502E−01 no Opioid Agonist kappa 7.5748 32 BRL

 hydrochloride −2.701 2.8549E−03 yes Neurotransmission Agonist kappa

7.7500 32 GR-

 fumarate −0.770 2.1800E−01 no Opioid Agonist kappa 0.0475 32 AC

 citrate 0.800 1.9065E−01 no Opioid Ligand kappa 3.3205 32 Flunarizine dihydrochloride −10.107 1.0242E−24 yes Dopamine Antagonist D1/D2 20.6718 130 Triflupromazine hydrochloride −9.305 6.6778E−21 yes Dopamine Antagonist D1/D2 17.0927 130 Triflupromazine hydrochloride −1.820 3.4349E−02 no Dopamine Antagonist DRD2 12.3307 130 Perphenazine −11.065 9.3020E−29 yes Dopamine Antagonist DRD2 18.2918 130 Prochlorperazine dimaleate −0.860 1.9485E−01 no Dopamine Antagonist 11.6765 130 Propionylpromazine hydrochloride −1.584 5.6571E−02 no Dopamine Antagonist DRD2 6.2928 130 cis-(2)-Flupenthixol dihydrochloride −8.822 5.59070E−10 yes Dopamine Antagonist DRD1/DRD2/A2a/ADRA1A 19.2805 130 Phenicamine maleate −0.205 4.1821E−01 no Histamine Antagonist HRH1 1.4913 100 (±)-Bromomphenicamine maleate −2.530 2.0756E−01 yes Histamine Antagonist HRH1 3.9172 100 (±)-Chlorphenicamine maleate −1.272 1.0706E−01 no Histamine Antagonist HRH1 3.9172 100 (−)-Bromophenicamine maleate −2.975 3.5057E−02 yes Histamine Antagonist HRH1 1.0173 100 (−)-Chlorphenicamine maleate −2.110 4.7135E−01 no Histamine Antagonist HRH1 1.0173 100 Disopyramide −4.179 1.4050E−05 yes K+ Channels Blocker 0.0502 100 Disopyramide phosphate −0.072 4.732E−01 no k+ Channels

5.2040 100 CGS-21680 hydrochloride −1.225 1.1027E−01 no Adenosine Agonist A2a 4.7849 132 5′-N-Ethylcarboxamidoadenosine −2.587 4.8437E−03 yes Adenosine Agonist A1/A2 1.5341 132 HE-NECA −2.504 6.1439E−03 yes Adenosine Agonist A2 12.7320 132 5′-n-Methyl carbomideadenosine −2.582 4.9052E−03 yes Adenosine Agonist A2 > A1 −0.1474 132 2-Phenylaminoadenosine 0.573 2.8340E−01 no Adenosine Agonist A2 > A1 1.7480 132 R(−)-2 10,11-Trihydroxy

−2.883 1.9695E−03 yes Adenosine Agonist A1 −2.8521 132 R(−)-2 10,11-Trihydroxy-N- −3.300 1.0546E−04 yes Dopamine Agonist DRD2 20.2733 54 Apomorphine hydrochloride

−11.274 3.3324E−03 yes Dopamine Agonist DRD2 29.7434 54 R(−)-

 hydrochloride −7.832 2.2697E−20 yes Dopamine Agonist 20.2434 54 R(−)-

 hydrochloride −7.839 2.2697E−10 yes Dopamine Agonist 30.0867 54 R(−)-

 hydrochloride −8.271 0.4584E−11 yes Dopamine Agonist DRD2 31.4575 54 R(−)-Apocodene hydrochloride −0.885 2.9450E−03 yes Dopamine Agonist 38.0005 54 Metoclopramide hydrochloride −1.992 2.3176E−02 no Dopamine Antagonist DRD2 7.3823 83 Tiapride hydrochloride 0.689 2.4543E−01 no Dopamine Antagonist D2/D3 4.0505 83 SDZ-205,557 hydrochloride −2.681 3.6740E−03 yes Serotonin Antagonist 5-HT4 10.9325 83 Procainamide hydrochloride 0.654 2.5871E−01 no Na+ Channel Antagonist 3.7651 83 N-Acetylprocainiamide hydrochloride −4.557 2.5891E−06 yes Na+ Channel Blocker 0.2381 83 N-(2-{4-(4-

benamide 0.383 3.5092E−01 no Dopamine Agonist D4 5.0521 83 Naloxone benzoylhydrazone 1.915 2.7727E−02 no Opioid Agonist kappa 2.3832 50 Naloxonazine hydrochloride 0.605 2.7223E−24 yes Opioid Antagonist 0.8582 50

 dihydrochloride −0.005 2.722−01 no Opioid Antagonist mp1 5.4107 50 Na

 hydrochloride 0.380 3.4860E−01 no Opioid Antagonist 0.5271 50

 hydrochloride 0.070 4.7107E−01 no Opioid Antagonist 0.3190 50 (−)-3-4-ethoxycarbonate hydrochloride 0.590 2.7547E−01 no Opioid Antagonist 1.8370 50 Cephapirin sodium 0.822 2.00

E−01 no Antibiotic Cell wall synthesis 1.8833 54 Cephalothia sodium 2.264 1.1788E−02 no Antibiotic Cell wall synthesis 4.6902 54 Cephalosporin O zinc salt −3.309 4.6797E−04 yes Antibiotic Cell wall synthesis 12.0888 54 Cefotaxime sodium −1.090 1.3

4E−01 no Antibiotic Cell wall synthesis 3.9918 54 Cefazolin sodium −2.580 4.

470E−03 yes Antibiotic Cell wall synthesis 19.8926 54 Cef

axane sodium 2.230 1.23

E−02 no Antibiotic Cell wall synthesis 1.1333 54 R(±)-UH-301 hydrochloride −2.517 5.0205E−02 yes Serotonin Agonist 5-HT1A 16.5801 127 S(−)-UH-301 hydrochloride −2.700 3.4078E−03 yes Serotonin Antagonist 5-HT1A 10.3601 127 R(±)-3-Hydroxy-DPAT hydrochloride −0.050 2.4100E−01 no Serotonin Agonist 5-HT1A 9.7005 127 (±)-5-Hydroxy-DPAT hydrobromide −0.050 2.5587E−01 no Serotonin Agonist 5-HT1A 9.7005 127 (±)-PPHT hydrochloride −1.915 2.77

E−02 no Dopamine Agonist 5-HT1A 0.0773 127 S(+)-Raclopride L-tartrate 1.901 2.

E−02 no Dopamine Antagonist DRD2 4.1295 126 S(−)-IBZM −0.117 4.53

E−01 no Dopamine Ligand DRD2 5.4292 126 (−)-Sulpiride −2.647 4.0

E−03 yes Dopamine Antagonist DRD2 7.5872 126 (±)-Sulpiride −0.2684 3.8816E−01 no Dopamine Antagonist DRD2 7.5872 126 S-(−)-E

 hydrohloride −5.158 1.3497E−07 yes Dopamine Antagonist DRD2 14.6402 126 3-Tropanyl-1,5-dichloro

0.272 0.

27E−21 yes Serotonin Antagonist 5-HT3 10.0220 20 4-Chloro-3-alpha-diphenylmethoxypropane hydrochloride 0.272 1.9822E−20 yes Dopamine Blocker Receptor 12.5850 20

 hydrobromide 0.744 2.2844E−01 no Cholinergic Antagonist

1.3000 20 Benzamine mesylate 3.740

E−05 yes Cholinergic Antagonist

12.5809 20 Amino

−1.455

E−02 no Cholinergic Ligand

0.8555 20 SKF-265A hydrochloride −1.928 2.6951E−02 no Multi-Drug Resistance Inhibitor Microsomal oxidation 3.1837 20 PRE-084 1.311 9.4358E−02 no Opioid Agonist sigma1 4.7579 20 Carbetapentane citrate −8.021 5.2461E−10 yes Opioid Ligand sigma1 12.5359 20 Procaine hydrochloride 0.550 2.9111E−01 no Na+ Channel Blocker 1.0300 20

−1.109 1.3282E−01 no Spningopid Inhibitor Glucosytaerasmide syntnase 1.4567 20 GBR-12909 dihydrochloride −10.

E−20 yes Dopamine Inhibitor Reuptake 17.1542 110 GBR-12935 dihydrochloride −11.274

E−30 yes Dopamine Inhibitor Reuptake 17.4032 110 Diphenylhydromine hydrochloride 0.845

E−01 no Histamine Antagonist HRH1 0.0028 110

 hydrochloride 0.455

E−01 no Cholinergic Antagonist

4.7071 110 Dasepin hydrochloride −1.012 1.5600E−01 no Adrenoceptor Inhibitor Uptake 0.7541 67 Aminophine hydrochloride 0.707 2.3990E−01 no Adrenoceptor Inhibitor Uptake 2.9998 67 Chlorprothixene hydrochloride −5.088 2.7565E−07 yes Dopamine Antagonist DRD2 12.4473 67 Thiothiene hydrochloride −1.900 2.8770E−02 no Dopamine Antagonist D1/D2 12.4315 67 (−)-

 bromide 1(S)

−1.842 3.2731E−02 no GABA Antagonist GABAA 3.43484 58 (±)-

−0.190 4.2310E−01 no GABA Antagonist GABAA 15.5310 58 (±)-Hydrostate −0.850 2.0113E−03 no GABA Antagonist GABAA 17.7530 58

 hydrochloride −2.455

E−

yes Opioid Ligand 21.4022 58 Ritodrine hydrochloride −2.332 9.8562E−03 yes Adrenoceptor Agonist beta2 1.5332 53 R(−)-Denopamine −4.480 3.6321E−06 yes Adrenoceptor Agonist beta1 2.2360 53 DL-alpha-Methyl-p-tyrosine −3.908 4.6497E−05 yes Neurotransmission Inhibitor Tyrosine hydroxylase −0.1777 53 alpha-Methyl-CL-tyrosine methyl ester hydrochloride 0.370 3.5550E−01 no Neurotransmission Inhibitor Tyrosine hydroxylase 0.5989 53 LY-53.857 maleate 0.338 3.0701E−01 no Serotonin Antagonist 6-HT14-HT1C 0.3125 51 Mesto

 hydrochloride −2.100 1.5365E−02 no Dopamine Agonist 4.35314 51 Methagoine −4.342 1.0522E−06 yes Serotonin Antagonist 5-HT25-HT1D 14.2794 51 Pergolide

−2.057 3.9457E−03 yes Dopamine Agonist D2,D1 1.4240 51 Retinoic acid −0.855 1.9333E−01 no Apoplosis Activator 1.3311 22 13-cis-retinoic acid −1.469 7.0905E−02 no Transcription Regulator RAR-alpha, beta 1.3311 22 Retinoic acid p-hydroxymide −0.013 9.0821E−10 yes Cell Cycle Inhibitor 9.8493 22

1.571 5.8038E−02 no Cell Stress Inhibitor Antagonist 1.2987 22

 hydrochloride 0.475 3.1254E−01 no Histamine Antagonist HRH1 3.5283 18 Promisine hydrochloride −0.858 1.8723E−01 no Dopamine Antagonist DRD2 5.8057 18 10-(alpha-

−1.545 0.1222E−02 no Biochemistry Inhibitor

4.2801 18 Thoridaine hydrochloride 0.230 4.0057E−01 no Dopamine Antagonist D1, D2 7.4158 18 Clomipramine hydrochloride −0.844 1.9938E−01 no Serotonin Inhibitor Reuptake 0.4509 108 Chlarpromacine hydrochloride 0.751 2.2645E−01 no Dopamine Antagonist 9.8583 108 Clorgyline hydrochloride 1.520 6.4194E−02 no Neurotransmission Inhibitor MAO-A 0.3833 108 NG-Hydroxy-L-arginine acetate −10.958 3.0541E−01 yes Nitric Oxide

NOS −0.6344 104 L-2-amine

 acid −2.354 9.8095E−03 yes Glutamate Inhibitor Glutamate Synthasis −1.4913 104 alpha-

 acid 9.041 7.7797E−20 yes Nitric Oxide Inhibitor NOS 3.7996 104 ML-9 −0.322 6.7090E−21 yes Phosphorylation Inhibitor MLCK 17.0244 78 ML-7 −11.274 8.8620E−30 yes Phosphorylation Inhibitor MLCK 16.9035 78 HA-100 −0.692 2.4534E−01 no Phosphorylation Inhibitor PKA/FKC/MLCK 2.0402 78

−1.572 5.7997E−02 no Cholineric Agonist Nicotinic 1.3227 75

−0.526 2.0614E−01 no Cholineric Antagonist Nicotinic 0.8300 75

−10.034 1.0520E−20 yes Cholineric Antagonist Nicotinic 0.4190 75 NS 521 oxylate −11.274 5.8020E−20 yes Glutamate Modulatort

2.9508 55

−0.232 4.0514E−01 no Dopamine Antagonist DRD2 2.0490 55 Demperidane −1.525 6.3575E−02 no Dopamine Antagonist DRD2 2.2927 55

−11.244 1.3858E−29 yes Phosphorylation Inhibitor COX 15.1452 50 CGP-74514A hydrochloride −9.117 3.8510E−20 yes Phosphorylation Inhibitor CdK1 15.1452 50 Tyro

 AG 1478 1.870 3.0751E−02 no Phosphorylation Inhibitor EGER 3.1249 50 Firenperone 0.228 4.0987E−01 no Serotonin Antagonist 5-HT2 1.7303 48 LY-310,762 hydrochloride 0.051 4.7902E−01 no Serotonin Antagonist 5-HT1D 3.0520 48 Ketanserin tetrate −3.325 4.4160E−04 yes Serotonin Antagonist 5-HT2 6.5571 48

1.658 5.0898E−02 no Serotonin Antagonist 5-HTIE, 5-HT2 6.2477 33

1.473 7.0371E−02 no Dopamine Antagonist DRD2 1.5450 33 Methaoxamine hydrochloride −3.252 5.0508E−04 yes

Agonist alpha1 4.8450 33 Fhenamil methanesulfonne 1.485 0.8800E−02 no Na+ Channel Inhibitor

 sensitive 3.3719 14 Amiloride hydrochloride −0.799 2.1207E−01 no Na+ Channel Blocker

2.6795 14 3′,4′-Dichlorobenzamil −2.591 4.9275E−03 yes Ion Pump Inhibitor Na+/Ca2+ exchanger 11.4518 14 Metho

10.203 0.0325E−25 yes DNA Metabolism Inhibitor 31.7559 13 (−)Ame

8.754 1.5989E−16 Yes DNA Metabolism Inhibitor 31.7589 13

−9.763 0.0018E−03 yes Agonist Inhibitor

25.1012 13 cis-(±)-5-OH-PEZI hydrochloride −11.102 5.1185E−29 no Dopamine Agonist D3 1.3911 8 (±)-7-Hydroxy-DPAT hydrochloride −11.102 6.1185E−29 yes Dopamine Agonist D3 12.3042 8 R-(+)-7-Hydroxy-DPAT hydrobromide −2.593 4.7938E−02 yes Dopamine Agonist D3 12.3042 8

Chlorophenyl)-

 hydrochloride 1.795 3.5304E−02 no Serotonin Agonist 5-HT3 3.4518 130 1-Phenxy

−2.689 3.5890E−03 yes Serotonin Agonist 5-HT3 2.0508 130 U-09194A methane 1.255 1.0468E−01 no Dopamine Antagonist D3 2.9081 133 YS-035 hydrochloride 0.043 4.8281E−01 no Ca2+ Channel Blocker L-type 3.7365 133

 tetrate −8.004 2.5920E−10 yes Glutamate Blocker

11.1514 128 Ro-25-5931 hydrochloride 10.524 3.8394E−20 yes Glutamate Antagonist NMDA-NR2B 12.1100 120

 hydrochloride −2.644 4.0994E−03 yes Serotonin Inhibitor Reuptake 17.8169 122 BRL 15572 0.312 3.7764E−01 no Serotonin Antagonist 5-HT1D 1.9532 122 2′

−1.357 8.5880E−02 no Immune System Inhibitor Reverse Trans

1.8575 115

 hydrochloride 1.274 5.8620E−20 yes DNA Metabolism Inhibitor 4.9565 115

 hydrochloride −2.338 9.0932E−03 yes Imidazoline Antagonist I1 2.0987 113 Methoctramine tetrahydrochloride −7.012 1.1764E−12 yes Cholineric Antagonist M2 7.2873 113 3-Amino-1-procanesulfate acid 0.591 1.1070E−11 yes GABA Agonist GABA-A −2.1145 111 3-Aminopropylphosporic acid −2.331 2.8654E−03 yes GABA Agonist GABA-B −2.5454 111 Indomethacin morpholinylamide −3.398 3.3995E−04 yes Cannabinoid Ligand CB2 6.9161 105 Indomethacin −0.355 3.2081E−01 no Phosphorylation Inhibitor COX 0.4544 105 2,3-

−10.985 1.2595E−25 yes Cell Stress Modulator 3.2447 103

−1.095 1.2080E−01 no Phosphorylation Inhibitor

1.5944 103 Celactor −3.009 1.3115E−03 yes Antibiotic Cell wall synthesis 14.9709 100 Cephahalexin hydrate −2.955 3.5470E−05 yes Antibiotic Cell wall synthesis 13.0445 100

1.507 5.5918E−02 no Biochemistry Inhibitor

2.1263 91

−0.453 2.0363E−01 no Biochemistry Inhibitor

1.7783 91 7,7-Dimethyl-(5Z,82)-

 acid −3.045 1.1618E−03 yes Lipid Inhibitor PLA2/Lipoxygenase 4.7938 85 Citric acid −0.345 3.6507E−01 no Phosphorylation Activator PKC 0.1929 85

2.931 1.5002E−03 yes Cell Cycle Inhibitor Aldehyde dehydrogenase 7.0102 80

1.489 2.1957E−01 yes Phosphorylation Inhibitor Tyrosine kinase 1.5385 80 3-Methoxy-morphanin hydrochloride −7.714 6.0807E−15 yes Glutamate Antagonist 8.7457 79 Dextromethorphan hydrobromide manchydrate −0.793 2.1384E−01 no Glutamate Antagonist NMDA 2.8222 79

 analog C-14 linker 11.274 1.8625E−30 yes Phosphorylation Inhibitor PKC-alpha 23.1032 74

2.540 7.1408E−22 yes K+ Channel Blocker 22.8573 74 Chloroquine diphasphate 0.499 3.0880E−01 no DNA Intercalator DNA 5.2087 72

 dihydrochloride −0.712 1.3300E−22 yes Neurotransmission Inhibitor MAD 10.3953 72

 oxide 3.402 2.2444E−04 yes Cholineric Agonist Muscanic 3.5333 70

−1.505 4.7549E−02 no Cholineric Agonist Muscanic 3.5333 73 (+)-But

 hydrochloride −5.934 1.4790E−09 yes Dopamine Antagonist D2 > D1 23.5780 68 (+)-But

 hydrochloride −11.274 8.8520E−30 yes Dopamine Antagonist 23.5780 68

 chloride 10-005 2.0621E−24 yes Ion Pump Inhibitor Na-K-ATPase 20.0105 66

 chloride 10.571 0.9758E−27 yes Phosphorylation Inhibitor PKC 29.3180 66 Chloro

0.081 4.0761E−01 no DNA Intercalator 2.8857 84 Melphalan −3.907 4.6645E−05 yes DNA Metabolism Intercalator GCC 0.0225 64 L-7653141 −0.831 2.0205E−01 no Adenoceptor Antagonist alpha 1B 0.7451 57 Pra

scin hydrochloride 2.992 1.8551E−02 yes Adenoceptor Antagonist alpha1 14.2207 57 L-745,570 hydrochloride −11.274 8.8620E−30 yes Dopamine Antagonist D4 6.9747 44 L-750,557 trihydrochloride −1.184 1.1822E−01 no Dopamine Antagonist D4 0.9183 44 N-Vara

−0.029 8.0770E−03 yes

Ligand 0.1937 42

−10.003 7.4315E−24 yes

Agonist 0.3231 42 Acyctoris −1.215 1.1227E−01 no Immune System Inhibitor Viral DND synthesis 1.5140 40 Ganclctrys −8.939 1.9004E−19 yes Cell Cycle Inhibitor G2-M-checkpoint 5.7653 40 MD-20170 3.139 1.2743E−01 no Cell Cycle Inhibitor

1.2350 38 Z-L-Phe chloromethyl ketone 3.901 1.8594E−03 yes Biochemistry Inhibitor

 A-gamma 5.0325 38

−2.395 8.3057E−03 yes Prostaglandin Inhibitor COX-2 5.3913 35

−2.754 2.6841E−03 yes Antibiotic Frotonophone 5.6937 38

 sulfate −10.792 1.8712E−27 yes Cytoskeleton and ECM Inhibitor Tublin 54.7151 35

−9.395 2.8241E−21 yes Cytoskeleton and ECM Inhibitor Tublin 53.7145 35 U-74369G nucleate −8.942 1.9194E−19 yes Cell Stress Inhibitor 13.4525 31 U-83935 dihydrochloride 0.954 1.7004E−01 no Cell Stress Inhibitor 3.3297 31

11.147 3.7067E−29 yes Cytoskeleton and ECM Inhibitor 10.7107 15 Elopcside 11.102 0.1554E−02 yes Apoplosis Inhibitor Topo 2 32.8884 15 GR 127935 hydrochloride −1.061 1.3994E−01 no Serotonin Antagonist 5-HT1B/1D 0.0535 11 SB 224289 hydrochloride −4.780 6.5192E−07 yes Serotonin Antagonist 5-HT1B 22.2519 11 MG 024 10.010 7.9545E−27 yes Cholineric Antagonist Nicotinic 6.1540 4 N,N,N′-trimethyl-1-(4-trans

) 11.127 4.0237E−29 yes Cholineric Antagonist Nicotinic 7.1135 4 Arecidine hydrobromide −0.111 4.5561E−01 no Cholineric Agonist 3.3496 2 Arecidine propargyl water hydrobromide −9.931 1.5191E−23 yes Cholineric Agonist M2 5.4180 2 GR 113805 0.912 1.5501E−01 no Serotonin Antagonist 5-HT1 5.2510 134 DSP-1 hydrochloride 1.518 5.4450E−02 no Adrenoceptor Neurotoxin 0.0039 134

2.3840E−01 no Antibiotic Cell wall synthesis 0.0389 131

 sodium and hydrate 2.277 1.1404E−02 no Antibiotic Cell wall synthesis 0.2649 126 (R,R)-cis-Detryl

1.053 1.4519E−01 no Hormone Antagonist EP-beta 0.7849 125 Metaphe meth

−4.957 3.3952E−07 yes Opiold Antagonist sigma 13.5640 124 Betaine hydrochloride −2.668 3.8320E−02 yes Biochemistry Modulator 2.2762 123 Pen

−11.274 1.5709E−18 yes Glutamate Antagonist NMDA 7.4941 121 Iodoscatamide 8.704 3.7402E−01 yes Biochemistry Inhibitor 0.91463 120

−0.334 3.8020E−01 no Dopamine Agonist D3 0.4052 118

2.817 2.4232E−03 yes Cycle

Activator

0.2223 117 SB 204070 hydrochloride 5.886 1.9754E−03 yes

Antatonist 5-HT4 10.2357 110 Dutamidine −2.437 7.4054E−03 yes Angonist 11.4540 114

10.643 8.3778E−27 yes Phor Inhibitor FKC 12.2420 112 XK400 −9.355 4.1753E−21 yes Apoplosis Inhibitor

15.1540 110

−10.428 9.2210E−24 yes Apoplosis Activator 0.9996 107 m-Iod

2.504 0.1751E−03 yes Apoplosis Activator 5.1572 105 L-587-

 hydrochloride 9.150 2.7015E−20 yes Opiold Agonist sigma 1 9.5021 102

 hydrochloride −0.265 0.9930E−01 no Depamine Agonist DRD2 0.9738 101 1-(2-Chlorophenyl)-1-[4-chlorophenyl]-2,2-dichloro

−2.508 0.0751E−03 yes Hormone Inhibitor Corticosteroid 0.0772 99 Hydro

−3.049 1.1470E−03 yes Hormone Cortisol 1.7854 98

 hydrochloride −2.058

yes Ca2+ Channel Blocker 14.2851 97 GYKi 52456 hydrochloride −1.854 3.1192E−02 no Glinamate Antagonist

1.4009 96

−11.274 6.2520E−30 yes DNA-Metabolism Inhibitor 17.7420 95 PAPP 10.728 3.7791E−27 yes Sarolonin Agonist 5-HT1A 9.3713 94

 dihydrochloride hydrate −10633 1.0510E−26 yes Apoploids Activator 22.1670 93 5-Fluorocuraol −7.749 4.0212E−18 yes Cell Cycle Inhibitor Thymid

 synthatase 2.4320 92 Eliptaine −8.321 4.3598E−17 yes Cell Cycle Inhibitor CYP1A1

 Topoll 3.0215 90 SS 415285 −2.870 2.05175−03 yes Phosphocrystan Inhibitor GSK-3 13.0577 89 TMB-8 hydrochloride 1.207 4.3949E−02 no Intracellular Calcium Antagonist 0.8600 88 Guaridmethyl disulfide dihydrobromide −1.521 3.0505E−06 yes Nitric Oxide Inhibitor iNOS 3.2504 87

−1.042 1.7211E−06 yes Na+ Channel Blocker 13.7902 85 Caknidazelium chloride −8.582 1.0481E−18 yes Intracellular Calcium Inhibitor Ca2+ATPase 23.0956 82 (S)-(*)-Camptonecin −9.670 2.0264E−22 yes Apaptoxis Inhibitor Topol 14.3223 71 Brateldin A from Peniclaim

11.274

.2520E−30 yes Cytoskeleton and ECM Inhibitor Golgi apparanas 14.2446 77 Diphenylene

 chloride −10.058 3.8424E−24 yes Nitric Oxide Inhibitor iNOS 7.7854 76 2-Chloro-2-diaxy-D-glucose −2.354 9.0301E−03 yes Biochemistry Analog Glucose 5.2008 73 CGS-12055A malease −2.575 5.0073E−03 yes Serotonin Agonist 5-HT1B 10.1700 71 (+)-AUT hydrochloride −2.388 6.9866E−01 yes Nitric Oxide Inhibitor iNOS 2.7281 69 Reseipine −1.023 1.5310E−01 no Serotonin Inhibitor Uptake 1.1851 65 Mailsylyte hydrochloride −1.018 1.5439E−01 no Adrenoceptor Antagonist alprial 0.1103 63 Chlorothiazide −3.185 7.7549E−04 yes Biochemistry Inhibitor Caronic anhydrase 8.3425 62

 hydrochloride −11.274 6.8620E−30 yes DNA Repar Inhibitor Topol 13.9612 61 CHS 1102 −3.782 7.7642E−05 yes Glucamate Antagonist NUDA 12.3153 60 Colohiene 10.753 2.8583E−27 yes Cytoskeleton and ECM Inhibitor Tubulin 16.7429 56 BTCP hydrochloride 0.825 2.0164E−01 no Depamine Blocker Reuptake 2.4561 52 Benzamidine hydrochloride 1.000 6.5503E−02 no Biochemistry Inhibitor Reuptake 0.2080 49 Zapinest 2.505 6.1083E−03 yes Cyclo

Inhibitor PDE V 11.2791 47 Carboplasm 0.284 2.7500E−10 yes DNA Inter

3.9150 46 2-(alpha-Naphthayl)ethylmethylammonium oxide 8.782 6.7869E−12 yes Cholineigic Inhibitor Choline Acetyltransferase 4.9215 45 SKF

5385 −1.497 3.4502E−00 yes Ca2+ Channel Inhibitor 10.6091 43 Antitabine hydrochloride −9.951 1.2427E−23 yes DNA Metabolism Inhibitor 10.7570 41 Azathioprine −7.213 1.2584E−15 yes P2 Receptor Inhibitor Pruine synthesis 8.9517 39 3′-Azido-3′-dearylaymidine −5.023 2.5440E−07 yes Immune System Inhibitor Reverse transcriptase 10.5585 37

−6.279 1.7125E−10 yes Antalate Inhibitor Rat. Rhd 17.6321 24 Thapslgargin −9.359 5.9519E−22 yes Intracellular Calcium Releaser 22.8512 20 Tarc −11.274 2.8520E−30 yes Cytoskeleton and ECM Inhibitor Tubulin 28.0485 28 Oxymetazoline hydrochloride −2.720 3.2562E−03 yes Adrenoceptor Agonist alpha

2.7662 27

 acid −2.479 7.7776E−03 yes Genemate Antagonist NMDA −1.2408 26 Soquzpiane −0.800 3.9970E−22 yes Gene Reputation Inhibitor Topo II 14.1485 25 TCPGEDP −2.008 2.2335E−02 no Transcriptor Agonist GAR 0.2981 24 Falcitene hydrochlorate −9.223 1.4500E−20 yes Hormone Molculer ER 17.4412 23 Raterne −11.274 8.8620E−30 yes Cet Strese Molculer Mocherides 17.3107 21 3-Methoxy-1,2,3,4-tetrahydro-3H-pyrido

2.501 3.8151E−03 yes Neurotransmission Inhibitor MAD 3.5170 18

−3.273 2.4793E−10 yes

Inhibitor Na+ CF transport 12.9520 16 SKE-804

0.852 5.8383E−01 no Adrenaceptor Antagonist Alpha2 2.2300 17 1-Anticyclopropane-carternyl

 hydrochloride −2.401 5.1070E−03 yes Glutamate Agonist NMDA-Glycrine −0.7432 12 SB 218783 −2.512 5.5103−03 yes phosphenyltation Inhibitor GSH-2 11.5423 10 Adenasine −5.501 3.3141E−04 yes Biochemistry Inhibitor

10.0832 9 2-Methyl

 diphosphate-trisodium 10.350 1.9058E−05 yes P2 Receptor Agonist P2Y 2.5127 7 NS-2025 2.0

3.0412−03 yes Cyclo

Inhibitor Gultamate cyetase 9.0194 6 Probephenyl IX-

−3.441 2.0302E−04 yes Cyclo

Activator

24.5208 5 Oligemyeln A −8.721 1.1127E−23 yes

Inhibitor 32.1070 3

−10.205 0.3130E−23 yes DNA Metabelism Inhibitor 2.117 1 MRS 1754 0.927 1.7702E−01 no Adenosine Antagonist A2B −18.0505 2-methoxyestradiol −0.983 1.6273E−01 no Hormone Metabolite Estrogen −11.8404 Cysteamine hydrochloride −0.599 2.7463E−01 no Somatostatin Depleter −2.3036 alpha,beta-Methylene adenosine 5′-triphosphate dilithium −1.290 9.8601E−02 no P2 Receptor Agonist P2X > P2Y −3.6150 D-Methylserctonin hydrochloride −0.172 4.3173E−01 no Serotonin Agonist −13.8908 Se-(methyl)selenocysteine hydrochloride 0.412 3.4032E−01 no Cell cycle Inhibitor −3.9644 Myricetin −0.911 1.8105E−01 no Phosphorylation Inhibitor Casein Kinase II −13.2584 NG-Monomethyl-L-arginine acetate −1.386 8.2827E−02 no Nitric Oxide Inhibitor NOS −5.3300 MK-912 −0.562 2.8028E−01 no Aderenoceptor Agonist alpha2A −2.8535 (±)-3-(3,4-dihydroxyphenyl)-2-methyl-DL-alanine −1.894 2.9132E−02 no Neurotransmission Inhibitor L-aromatic amino acid dec −6.9387 MRS 2169 −0.267 3.9489E−01 no P2 Receptor Antagonist P2X1 −14.3488 2,6-Di

4-[2-4phyenlsulfinylamino)ethylthio]phenoxyacetamide −0.498 3.0915E−01 no Glutamate Agonist AMPA −7.6987 Lorglomide sodium −2.092 1.8225E−02 no Cholecystockrin Antagonist CCK-A −4.4235 LY-278,584 maleate −1.074 1.4143E−01 no Serotonin Antagonist 5-HT3 −5.9712 R(+)-Lisunide hydrogen maleate −1.041 1.4905E−01 no Dopamine Agonist DRD2 −23.9479 L-703,606

−0.507 3.0612E−01 no Tachykinin Antagonist NK1 −1.7783 Levallophan tartrate −0.346 3.6450E−01 no Opioid Antagonist −0.6160 S-(−)-Lisuride −0.147 4.4144E−01 no Dopamine Agonist DRD2 −21.7059 Linopirdine −0.553 2.9029E−01 no Cholinergic Releaser −7.9848 L-741,626 −1.009 1.5639E−01 no Dopamine Antagonist DRD2 −11.7935 L-733,060 hydrochloride −1.465 7.1425E−02 no Tachykinin Antagonist NK1 −1.2037 R(−)-Me5 −1.414 7.8639E−02 no Na+ Channel Antagonist −3.4341 (−)-Naproxen sodium 0.502 2.7345E−01 no Prostaglandin Inhibitor COX −7.5011 (−)-Methylpropyl hydrochloride 1.042 1.4861E−01 no Biochemistry Inhibitor Alcohol dehydrogenase −5.4206 Nocodazine −0.189 4.2502E−01 no Cytoskeleton and ECM Inhibitor beta-tubulin −8.4905 N-omega-Methyl-5-hydroxylptamine oxalate salt 0.556 2.5593E−01 no Serotosia Ligand −21.3103 Moxonidine hydrochloride 0.217 4.1407E−01 no Aderenoceptor Agonist alpha2A −9.0361 MRS 1845 −0.006 4.9753E−01 no Ca2+ Channel Inhibitor SOC −8.9172 N-Methyl-1-deoxynojninaycin −1.335 9.0866E−02 no Biochemistry Inhibitor Glucosidase −4.4000 MRS 1523 −0.001 4.9948E−01 no Adenasine Antagonist A3 −6.3328 Metaproterenol hemisulfate −1.022 1.5345E−01 no Adrenoceptor Agonist beta2 −10.9972 Mianserin hydrochloride 0.975 1.8439E−01 no Serotonin Antagonist −3.8848 8-Methoxymethyl-3-isobutyl-1-methylxythine −0.340 3.0383E−01 no Cyclic Nucleotides Inhibitor PDE1 −11.1580 MK-886 −1.549 6.0662E−02 no Leukotriene Inhibitor −12.4571 Mexiletene hydrochloride −1.259 1.0406E−01 no Na+ Channel Blocker −4.9652 Methylergonovine maleate −0.785 2.1635E−01 no Dopamine Antagonist −21.8872 Molsidomine 1.567 5.8608E−02 no Nitric Oxide Donor −7.5890 3-Methyl-5-[3-trifluoromethylphenyl]−1,2,4-triazolo[4,3-b]pyridazine 0.091 4.6377E−01 no Benzodiazepine Agonist BZ1 −3.2042 Mizorbine 1.542 5.0274E−02 no DNA Metabelism Inhibitor IMP dehydrogenase −5.7895 S-Methylisothiourea hemisulfate −0.211 4.1540E−01 no Nitrio Oxide Inhibitor NOS −1.3890 N-Methyl-D-aspartic acid −1.860 3.1415E−02 no Glutamate Agonist NMDA −3.3399 MJ33 1.364 8.6259E−02 no Lipid Inhibitor PLA2 −10.6297 MRS 2179 −1.246 1.0638E−01 no P2 Receptor Antagonist P2Y1 −10.4540 Meloxicam sodium −1.140 1.2723E−01 no Prostaplantin Inhibitor COX-2 −4.9935 Morin −2.216 1.3362E−02 no Cell Stress Inhibitor Antioxidant −8.1816 Minoxidil −1.189 1.1715E−01 no K+ Channel Activator ATP sensitive −4.7999 Meclofernomic acid sodium 2.233 1.2790E−02 no Prostaglarfin Inhibitor COX/5-Lipoxygenase −0.5636 Mikinine 0.055 4.7805E−01 no Cyclic Nucleotides Inhibitor PDE III −13.5090 (±)-alpha-Methyl-4-carboxyphenylglycine 0.727 2.3362E−01 no Glutamate Antagonist Metabotropic −7.9747 1-Methylhistamine dihydrochloride 0.307 3.7950E−01 no Histamine Metabolite −5.4372 S-Methyl-L-thiocitroluine acetate −1.751 3.9585E−02 no Nitiric Oxide Inhibitor NOS −5.2887 Melatonin −0.241 4.0480E−01 no Melatonin Agonist −15.8002 L-Methionine sulfoximine 0.057 4.6545E−01 no Glutamate Inhibitor Glutamine synthase −4.8953 (±)-Metoprolol (+)-tartate −0.269 3.9

E−01 no Adrenoceptor Antagonist beta1 −15.9164 5-Methyl-2-(phenylethynyl)pyridine hydrochloride 0.094 4.

E−01 no Glutamate Antagonist mGluR5 −4.7043 Mibefradis dihydrochloride −0.027 4.8

E−01 no Ca2+ Channel Blocker T-type −8.5973

nosine 0.742 2.2

E−01 no Adenasine Agonist −6.9910 (S)-MAP4 hydrochloride −0.553 2.9

E−01 no Glutamate Antagonist mGluR4.6.7 −4.5665 (±)-Methoxtverapanil hydrochloride −1.407 7.9775E−02 no Ca2+ Channel Antagonist L-type −1.2039 Metrazoline oxalate 0.107 4.5728E−01 no Imidazoline Ligand −8.0272 GW9582 1.475 7.0158E−02 no Transcription Inhibitor PPAR-gamma −6.3283 Sodium Taurocholate −0.760 2.2352E−01 no Multi-Drug Resistance Modulator Conjugate Pathway −13.7869 Amiiostine 0.359 3.5974E−01 no Cell Stress Inhibitor Cytoprotectant −5.7141 Acetazolemide 1.111 1.3326E−01 no Biochemistry Inhibitor Carbonic anhydrase −3.7190 A-315456 0.383 3.5835E−01 no Adrenoceptor Antagonist alpha1D −5.5278 GR-4651 0.102 4.5957E−01 no Serotanin Agonist 5-HT1D −11.8529 2-Hydroxysaclofan −1.624 5.2176E−02 no GABA Antagonist GABA-B −3.8385 Nicardipine hydrochloride 1.860 3.0818E−02 no Ca2+ Channel Antagonist L-type −17.3875 Nifedipine −0.294 3.8448E−01 no Ca+ Channel Antagonist L-type −12.3093 7-Nitroindazole −1.349 8.8727E−02 no Nitric Oxide Inhibitor nNOS −9.4168 6-Nitraso-1,2-benzopyrone 0.011 4.9549E−01 no Transcription Inhibitor PARP −6.2052 Nilutamide 0.119 4.5278E−01 no Hormone Inhibitor Androgen −5.4365 NF 023 1.115 1.3250E−01 no P2 Receptor Antagonist P2X1 −15.4323 Nim

 hydrochloride −0.652 2.5707E−01 no DNA Intercalator −6.1040 Norc

−1.251 1.0549E−01 no Phosphorylation Inhibitor PP2A −2.1578 (+)-Niootin (+)-di-p-lotuayl tartrate −2.233 1.2776E−02 no Chalinergic Agonist Nico

−5.5323 N

 hydrochloride −0.314 3.7675E−01 no Opiaid Antagonist delta −6.3412 N-(p-[

phenyl]spiperone hydrochloride −0.415 3.3899E−01 no Dopamine Antagonist DRD2 −3.6574 NO-711 hydrochloride −0.452 3.2213E−01 no GABA Inhibitor Uptake −2.5809 Atropine methyl bromide −0.972 1.9172E−01 no Chalinergic Antagonist Muscaferio −16.1459 Amperoxide hydrochloride −0.413 3.3993E−01 no Seratonin Ligand −2.3932 Aminoguandine hemisulfate −1.219 1.1135E−01 no Nitric Oxide Inhibitor NOS −3.7822 Agmatine sulfate 0.588 2.7823E−01 no Imidazoline Agonist −3.1654 4-Aminobenzamidine dihydrochloride −1.287 9.9097E−02 no Biochemistry Inhibitor Trypsin −1.1605 Mitepristone −1.970 2.4404E−02 no Horomone Antagonist Frogestone −8.2079 L-alpha-Methyl-p-tyrosine −1.800 3.5928E−02 no Neurotransmission Inhibitor Tyrosine hydroxylase −0.1777 Mona

−1.152 1.2280E−01 no Cell Cycle Inhibitor EgG5 −10.4422 1-Methylfamidazole −0.847 1.9852E−01 no Prostagiondin Inhibitor COX −2.1232 Mecemylamina hydrochloride −2.108 1.7531E−02 no Chalinergic Antagonist Nicotinic −6.6672 Methapyrilene hydrochloride 0.528 2.0514E−01 no Histamine Antagonist HRH1 −6.5557 Memantine hydrochloride −0.141 4.4392E−01 no Glutamate Antagonist NMDA −2.7403 Me-3,4-dephostatin 0.583 2.7980E−01 no Phosphorylation Inhibitor PP1B/SHPTP-1 −7.1731 Minocycline hydrochloride 0.442 3.2929E−01 no Cell Cycle Inhibitor −11.6737 Mapropeline hydrochloride −0.351 3.5888E−01 no Adrenoceptor Inhibitor Reuptake −5.6469 H-8 dihydrochloride −1.583 5.6734E−02 no Phosphorylation Inhibitor PKA, PKG −12.8845 Proglumide −1.907 2.8236E−02 no Cholecystokinin Antagorist −0.7173 (±)-Muscarine chloride −1.905 2.8377E−02 no Cholinergic Agonist Muscarinic −4.2822 (+)-MK-801 hydrogen maleate −0.098 4.6095E−01 no Glutamate Antagonist NMDA −7.4893 (−)-MK-801 hydrogen maleate 1.133 1.2852E−01 no Glutamate Antagonist NMDA −7.4893 2-Meyhyl-5-hydroxytryptamine maleate 0.572 2.8372E−01 no Serotonin Agonist 5-HT3 −11.8280 alpha-Methyl-5-hydroxytryptamine maleate −0.780 2.1782E−01 no Serotonin Agonist 5-HT3 −20.4376 L-alpha-Methyl DOPA −0.897 1.8485E−01 no Biochemistry Inhibitor Aromatic amino acid decar −6.9387 Methysergide maleate −0.020 4.9209E−01 no Serotonin Antagonist −8.8270 Methyltetramyl

 chloride 1.913 2.7879E−02 no Cholinergic Agonist Nicotric −8.1124 MDL 26.530 trihydrochloride 0.327 3.7170E−01 no Glutamate Agonist NMDA-Polyamine −4.5631 ZM 3P933 hydrochloride 0.746 2.2793E−01 no Phosphorylation Inhibitor JNF-3 −2.5434 3-MorphoEnoxy

amine hydrochloride −1.324 9.2801E−02 no Nitric Oxide Donor −5.4749 p-MPFI hydrochloride 0.261 3.9720E−01 no Serotonin Antagonist 5-HT1A −9.5404 MDL 105,510 2.555 5.1579E−03 no Glutamate Antagonist NMDA-Glycine −6.9319 Metri

−0.212 4.1594E−01 no Adenosine Agonist A2 −6.6255 p-MPPF dihyrochloride −2.160 1.5404E−02 no Serotonin Antagonist 5-HT1A −9.0044 Niethumic acid −1.958 2.5127E−02 no Prostaglandin Inhibitor COX-2 −8.2950 Nialamide −0.029 4.8829E−01 no Neurotransmission Inhibitor MAO −7.2108 Nomifensine maleata 0.669 2.5166E−01 no Deparaise Inhibitor Reaptak −8.0207 nor-Binaltorphimine dihydrochloride 0.388 3.4898E−01 no Opioid Antagonist lappa −5.3339 Neostigerine bromide 1.228 1.0966E−01 no Challinergic Inhibitor A

linesterase −5.7277 CR 2249 −1.002 1.5523E−01 no Glutamate Agonist NMDA-Glycine −6.4049 S-(4-Nitrobenzyl)-6-thicinosine −0.427 3.3404E−01 no Adenosine Inhibitor Uptake −10.0990 S-Nitro-N-acetylpheni

−1.045 4.0050E−02 no Nitric Oxide Donor −5.3835 NAN-

-hydrochloride −0.010 2.0503E−01 no Serotonin Antagonist 5-HT1A −8.5603 NCS-326 2.833 2.3079E−03 no GABA Agonist gamma-Hydrocybuyrate −5.1409 S-Nitrosoglutathione

2.4250E−01 no Nitric Oxide Donor −9.5229 NCS-382 −1.733 4.1521E−02 no GABA Antagonist gamma-Hydrocybuyrate −4.9225 Nalidixic acid sodium −0.314 3.7659E−01 no Antibiotic Inhibitor DNA Gyrase −12.610 5-Nitro-2-(3-phenylpropyleneamino)benzoic acid −0.734 2.3139E−01 no CI-Channel Blocker −7.9444 NF449 octasodium salt 1.851 3.2049E−02 no G protein Antagonist G5-alpha −13.0359 Nordihydroguaisretic acid from Lacrea divaicala (crecscls bush) 2.630 4.2730E−03 no Leukotriene Inhibitor Lipoxygenase −6.6401 (−)-Nicotine hydrogen tartrate salt 0.045 4.8208E−01 no Cholinergic Agonist Neuotric −3.2819 NG-Nitro-L-arginine 0.139 4.4492E−01 no Nitric Oxide Inhibitor NOS −7.8438 Naphazoline hydrochloride −1.724 4.2333E−02 no Adrenoceptor Agonist alpha −4.9453 3-Nitropropinic −0.563 2.8557E−01 no Cell Stress Toxin −4.6291 NG-Nitro-L-arginie methyl ester hydrochloride −1.411 7.0178E−02 no Nitric Oxide Inhibitor NOS −5.3340 (±)-Nomnetanephrine hydrochlodride −1.795 3.6219E−02 no Adrenoceptor Metabolite Narepinephyrine −2.4055 Nortriptyline hydrochloride −1.095 1.3659E−02 no Adrenoceptor Inhibitor Uptake −4.0728 NADPH tetrasodium 0.302 3.8123E−01 no Nitric Oxide Cofactor −10.4977 Valproio acid sodium −0.095 4.0213E−01 no Anticonvulsant −4.3774 Fraziquantel −2.296 1.0539E−02 no Antibiotic Ca2+ Ionophore −6.6721 Propafenone hydrochloride −0.957 1.8870E−01 no K+ Channel Blocker hKv1.5 −12.0390 5alpha-Pregnan-3alpha-ol-11,20-dione −0.609 2.0905E−01 no GABA Modulator GABA-A −14.4850 Pespidine tartrate −1.719 4.2625E−02 no Cholinergic Antagonist Niectinle −2.92296 Piracetam −0.376 3.5353E−01 no Glutamate Modulator Niectinle −7.7089 Phosphomycin disodium −1.402 8.0513E−02 no Antibiotic Cell wall synthesis −4.3038 Pyrilamine maleate 0.989 1.6127E−01 no Histamine Antagonist HRH1 −6.9749 Piroxicam 0.253 4.0025E−01 no Prob

din Inhibitor COX −7.4543 3-n-Propyl

−1.094 1370E−01 no Adenosine Antagonist A1 > A2 −11.5800 Phenylphrine hydrochloride −1.257 1.0442E−01 no Adrenoceptor Agonist alpha1 −11.1360 Pentylenetetrazole −0.927 1.7635E−01 no Neurotransmission Modulator CNS −3.7535 (+)-Pilocarpine hydrochloride −1.549 6.082E−02 no Cholinergic Agonist Muscarinio −3.6587 Pilocarpine nitrate −1.213 1.1256E−01 no Cholinergic Agonist Muscarinio −5.4850 Nitrodipine −1.610 5.3738E−02 no Ca2+ Channel Antagonist L-type −18.7148 Nitrodipine −0.854 2.0228E−01 no Ca2+ Channel Antagonist L-type −11.0786

 hydrochloride 0.834 2.0226E−01 no Adrenoceptor Blocker Reaptake −11.0438

 hydrochloride −1.375 8.4499E−02 no Adrenoceptor Agonist beta −0.0022 N5-Cyclopentyl-9-methyladerine −2.112 1.7347E−02 no Adenasine Antagonist A1 −3.0271 Naltriben methanesulfonate −0.381 35.920E−01 no Opicid Antagonist delta2 −6.1337 Naftopicil dihydrochloride −0.117 4.5334E−01 no Adrenoceptor Antagonist alpha1 −12.5115 BW 245C 1.036 1.5017E−01 no Prostarioids Agonist DP −6.5950 NS-1619 −0.468 3.1285E−01 no K+ Channel Activator CA2+ activated −0.7044 NBQX disodium −1.675 4.6988E−02 no Glutamate Antagonist AMPA/kainate −8.4171 (±)-Ostoparmine hydrochloride −1.567 5.8506E−02 no Adrenoceptor Agonist alpha −2.8789 N-Diecylthanolamine −0.412 3.4030E−01 no Sphingolipid Inhibitor Ceramidase −2.3589

 acid 0.918 1.7933E−01 no Antibiotic Inhibitor DNA Gyrase −2.8871

1.553 6.0230E−02 no Phosphorylation Inhibitor PK −3.5670 Sodium Oxamate 0.745 2.2817E−01 no Biochemistry Inhibitor Lactate Dehydrogenase −4.3313 Oxybutynin Chloride 0.708 2.3948E−01 no Cholinergic Antagonist Muscarinic −4.4857 Oxiracetam −0.613 2.6992E−01 no Neotrepic −5.2602 Ouabain −1.568 5.8446E−02 no Ion Pump Inhibitor Na+/K+ ATPase −5.3647 ODQ −0.592 2.7686E−01 no Cyclic Nucleotides Inhibitor No-sensitive guanylyt cye −3.1837 Oficxacin −0.489 3.1247E−01 no Antibodies DNA Synthesis −6.7858

 sesquifumarate salt 0.855 1.0823E−01 no cholinergic Agonist M2 −8.1581 Oxatomide 0.596 2.7568E−01 no Immune Systems Mocluator −1.1963 Oxaprozin 0.066 4.7363E−01 no Prostrsgilairdin Inhibitor −4.2022 Oxotremaine methiodide −0.700 2.4191E−01 no Cholinergic Agonist Muscarinic −8.3627 Progesterens 0.425 3.3535E−01 no Hormone Progesterone −12.7899 Palmitcylathnolamide −0.913 1.8051E−01 no

Agonist CB2 −2.3737 Piceal

0.595 2.7587E−01 no Phosphorylation Inhibitor Syk/Lck −10.2033 Parthenolide −0.724 2.3459E−01 no Serotonin Inhibitor −4.0788 Pindolol −0.079 4.6853E−01 no Adrenoceptor Antagonist beta −25.5497 O-Phospho-L-serine 0.547 2.9212E−01 no Glutamate Antagonist NMDA −6.3290 (±)-Proprano

 hydro

0.357 3.8305E−01 no Atranoceptor Antagonist beta −17.1649 Ficro

0.777 2.1855E−01 no GABA Antagonist GABA-O −3.0384 4-Phenyl-3-

0.931 1.7584E−01 no Nitric Oxide Doner −6.6935 Pectaxthylane −1.637 5.0810E−02 no Cyclic Nucleotides Inhibitor PDE −16.7236 L-Glutamic acid, N-phthaloyl- −0.589 2.7788E−01 no Glutamate Agonist NMDA −4.9887 Pancuronium bromide 0.408 3.4176E−01 no Cholinergic Antagonist −12.6977 3-alpha,21-Dhydroxy-5-alpha-pergnan-20-one 0.444 3.2849E−01 no GABA Modulator GABA-A −15.4033 Pirfenidone −1.482 6.9175E−02 no Immune System Inhibitor −1.4000 1,3-Dimethyl-B-phenylxanthine 0.752 2.2509E−01 no Adenasine Antagonist A1 −19.9006 PPNDS tetrasodium −2.067 1.9369E−02 no P2 Receptor Antagonist P2X1 −17.6537 PD 404,182 0.091 4.6392E−01 no Biochemistry Inhibitor KDO-8-P synthase −4.8559 Papaverine hydrochloride −0.299 3.8240E−01 no Cyclic Nucleotides Inhibitor PDE −1.5223 Pantolinium d-[L(+)-tartrate] 0.166 4.3402E−01 no Cholinergic Antagonist Nicotinic −4.6241 1-Phenyl-3-(2-thiazolyl)-2-

1.208 1.1348E−01 no Cholinergic Inhibitor beta-Hydroxylase −7.0804 Thiolactomycin −1.300 9.5869E−01 no Antibiotic Inhibitor Myristine synthesis −4.4790 Cisplatin 1.523 6.3908E−02 no DNA Intercalator −1.2254 Palmitoyl-DL-Carnitine chloride 0.200 4.2092E−01 no Phosphorylation Modulator PKC −2.9027 R(−)-N6-(2-Phenylisopropyl)Adenasine −2.023 2.1549E−02 no Adenasine Agonist A1 −5.5885 N-Phenylantyranitric acid −1.610 5.3659E−02 no CI-Channel Blocker −6.7826 S(−)-p-

−1.295 9.7578E−02 no Phosphorylation Inhibitor Alkaline phosphatase −8.7258 5-Aminoactera and hydrochloride −1.670 4.7454E−02 no GABA Antagonist GABA-B −2.9370 (±)-Nipecotic acid −0.722 2.3529E−01 no GABA Inhibitor Uptake −4.7970 Azelaic acid 0.106 4.5792E−01 no DNA Metabelism Inhibitor −1.4943 Tryptamine hydrochloride 1.245 1.0658E−01 no Serotin Ligand −15.7942 5-Fluoroindole-2-hydroxy acid −0.008 4.9699E−01 no Glutamate Antagonist NMDA-Glycine −8.5717 PD 168,077 maleate −1.516 6.4777E−02 no Depamine Agonist D4 −2.9614 SU 6658 0.316 3.7553E−01 no Phosphorylation Inhibitor Sre family kinase −2.8895 Quercudin dihydrate −2.302 1.0654E−02 no Cyclic Nucleotides Inhibitor PDE −14.2835 Quinidine sulfate −1.930 2.6809E−02 no Na+ channel Antagonist −0.1268 Qutparine

−1.444 7.4350E−02 no Serotonin Agonist −10.3024 Quazinene sulfate −0.269 3.9413E−01 no K+ Channel Antagonist −0.1268 [+]-Quinipirate hydrochloride 0.436 3.3137E−01 no Glutamate Agonist AMPA −5.8739 Quaziene 0.205 4.1894E−01 no Cyclic Nucleotides Inhibitor PDE III −4.2156 [−]-Quinipirate thydrochloride −1.565 5.8745E−02 no Dopamine Agonist D2/D3 −8.0415 Quipacine, N-methyl-. dimaleate −0.325 3.7242E−01 no Serotonin Agonist 5-HT3 −5.2567 Quiparine, 6-nitrio-. malate 0.978 1.6400E−01 no Serotonin Inhibitor Reuptake −14.7827 Queneorane hydrochloride −1.567 5.8557E−02 no Dopamine Agonist DRD2 −5.7572 [±]-Quinipirate thydrochloride −0.451 3.2590E−01 no Dopamine Agonist D2 > D3 −6.9743 Cortexotone −0.609 2.7135E−01 no Hormone Precursor Cortisol −10.9265 Phenelzine sulfate −1.536 6.2233E−02 no Neurotransmission Inhibitor MAO-A/B −4.6157 Phosphonoacetic acid −0.888 1.8714E−01 no DNA Inhibitor DNA Polymerase −3.1115 (−)-Penilic acid −1.321 9.3323E−02 no G protein Inhibitor p21 Ras −5.2521 Pyrazinecarboxamide −1.617 5.2920E−02 no Antibiotic −4.8113 Pricidone 0.619 2.6807E−01 no Anticonvelsant −4.0977 Pinerzepine dihydrochloride −0.545 2.9289E−01 no Cholinergic Antagonist M1 −3.8093 Putoscine dihydrochloride −0.769 2.2096E−01 no Glutamate Agonist NMDA-Polyamine −2.3789 Phentalamine mesylate −0.319 3.7483E−01 no ADrenoceptor Antagonist alpha −7.3473 Phlexalin 0.916 1.7971E−01 no Ca2+ Channel Blocker L-Type −2.5179 Pargyline hydrochloride −0.279 3.6998E−01 no Neurotransmission Inhibitor MAO-B −2.0187 Phorben 12-myristate 13-acetate −0.265 3.9551E−01 no Phosphorylation Activator PKC −2.8220 1,3-PEIT hydrobromide 2.221 1.3159E−02 no Nitric Oxide Inhibitor NOS −4.5252 1,4-PEIT ehydrobromide −1.179 1.1014E−01 no Nitric Oxide Inhibitor NOS −5.7763 Phenylbutane 0.790 2.1470E−01 no Prostaglandin Substrate Prostaglamin peroxidase −3.3633 Piootamide 1.736 4.1318E−02 no Thromboxane Antagonist TXA2 −1.0308 Traanylcypromine hydrochloride −1.441 7.4837E−02 no Neurotransmission Inhibitor MAO −6.3559 (S)-Propea

 hydrochloride −0.535 2.9645E−01 no Adrenoceptor Blocker beta −17.1649 Ammonium pyrrolidinedithiocarbamata −0.417 3.3543E−01 no Nitric Oxide Modulator NOS −5.9065 (±)-ois-Piperidine-2,3-dicarboxylic acid 0.155 4.3829E−01 no Glutamate Agonist NMDa −7.4174 Protriptyline hydrochloride 0.760 2.2355E−01 no Adrenoceptor Blocker Reuptake −6.9557 5(5H)-Phen

0.677 2.4936E−01 no Transcription Inhibitor PARP −1.7136 5alpha-Pregnan-3alpha-ol-20-one 0.934 1.7527E−01 no GABA Modulator GABA-A −15.2536 Propentheline bromide −1.534 6.2542E−02 no Cholinergic Antagonist Muscarinic −4.4811 Piperidine-4-sulphonic acid −0.424 3.3588E−01 no GABA Agonist GABA-A −2.9963 Paramomycin sulfate 0.821 2.0582E−01 no Antibiotic Protein synthesis −4.4506 1,10-Phenanthroline monohydrate −0.886 1.8793E−01 no Biochemistry Inhibitor Metalloprotease −3.3402 Prilocaine hydrochloride 1.509 6.5665E−02 no Na+ Channel Blocker −8.1733 Propentotylline 0.156 4.3790E−01 no Adenosine Inhibitor Transporter −15.1399 (S)-(−)-propafenone hydrochloride −0.752 2.2591E−01 no Adrenoceptor Blocker beta −12.0390 Pyridostigmine bromide 0.231 4.0862E−01 no Cholinergic Inhibitor Cholinesterase −1.7195 R(+)-3PPP hydrochloride −2.213 1.3452E−02 no Dopamine Agonist DRD2 −10.0895 S(−)-3PPP hydrochloride −0.421 3.3705E−01 no Dopamine Agonist DRD2 −10.0895 3-Phenylpropargylamine hydrochloride −2.043 2.0514E−02 no Dopamine Inhibitor Dopamine beta-hydroxylase −3.1720 N6-2-Phenylethyladenosine 0.531 2.9763E−01 no Adenosine Agonist A1 −7.1641 N6-Phenyladenosine 0.728 2.3320E−01 no Adenosine Agonist A1 −1.7086 P

0.970 1.0000E−01 no GABA Antagonist GABA-B −7.2387 (±)-Pindobind 0.257 3.9841E−01 no Adrenoceptors Ligand beta −24.1169 SKF P4836 0.245 4.0292E−01 no Calcium Signaling Inhibitor PDE III −11.6799 IC 261 −1.630 5.1562E−02 no Phosphorylation Inhibitor CK-1delta/epsilon −7.3987 S(−)-Pindolol −1.122 1.3093E−01 no Serotonin Agonist 5-HT1A −25.5497 Pinacidii −2.117 1.7149E−02 no K+ Channel Activator −11.3913 Pregnenolone sulfate sodium 2.653 3.9869E−03 no GABA Antagonist GABA-A −11.1447 PPADS 1.105 1.3440E−01 no P2 Receptor Antagonist P2 −14.7027 S(+)-PD 128,907 hydrochloride −1.174 1.2027E−01 no Dopamine Agonist D3 −2.1728 Phenylbenzene-omega-phosphono-alpha-amino acid −0.014 4.9432E−01 no Glycine Antagonist −0.7417 Phthalamoyl-L-glutamic acid trisodium 0.251 4.0096E−01 no Glutamate Agonist NLIDA −5.5159 PD 98,059 0.903 1.8334E−01 no Phosphorylation Inhibitor MEK2 −3.9645 (±)-PD 129,907 hydrochloride 1.164 1.2221E−01 no Dopamine Agonist D3 −2.1728 S-(4-Nitrobenzyl)-6-thioguanosine 0.102 4.5951E−01 no Adenosine Inhibitor −7.6238 4-Aminopyridine −1.516 6.4813E−02 no K+ Channel Blocker A-type −4.8117 Atropine sulfate 1.244 1.0672E−01 no Cholinergic Antagonist Muscarinic −4.7393 Atropine methyl nitrate 1.292 9.8265E−02 no Cholinergic Antagonist Muscarinic −17.8825 Areaine sulfate −0.330 3.7075E−01 no Glutamate Antagonist NMDA-Polyamine −1.0169 Sphingosine 1.404 8.0132E−02 no Phosphorylation Inhibitor PKC −1.5940 SB 209970 hydrochloride −1.100 1.3570E−01 no Serotonin Antagonist 5-HT7 −1.6559 Spiperone hydrochloride −0.517 3.0260E−01 no Dopamine Antagonist DRD2 −7.9131 SR 2640 −1.548 6.0825E−02 no Leukotriene Antagonist CysLT1 −9.7171 (−)-Scopolamine, n-Butyl-, bromide 0.649 2.5831E−01 no Cholinergic Antagonist Muscarinic −16.9994 SB 205384 0.797 2.1277E−01 no GABA Modulator GABA-A −8.6705 CV-3998 −0.437 3.3102E−01 no Cytokines & Growth Fa Antagonist PAF −6.2993 S

dac −0.194 4.2302E−01 no Prostaglandin Inhibitor COX −8.2302 Succinylcholine chloride −1.933 2.6777E−02 no Cholinergic Antagonist Nicotinic −4.6390 Salbutanol −1.678 4.6677E−02 no Adrenoceptor Agonist beta2 −8.6603 Salme

ol −9.493 3.1222E−01 no Adrenoceptor Agonist beta2 −8.8943 SU 5416 −0.002 2.5394E−01 no Phosphorylation Inhibitor VEGFR PTK −10.8964 (−)-Scopolamine methyl bromide −0.847 1.9854E−01 no Cholinergic Antagonist Muscarinic −16.9163 Ruthenium red −0.074 4.7055E−01 no Ion Pump Inhibitor Mitochondrial uniporter −0.9840 Rutaecarpine 0.888 2.4845E−01 no K+ Channel Blocker −7.8454 Resveratrol −0.230 4.0924E−01 no Prostaglandin Inhibitor COX −3.8617 REV 5901 −1.184 1.1813E−01 no Leukotriene Antagonist LTD4 −7.0078 Rottlerin 0.304 3.8047E−01 no Phosphorylation Inhibitor PKC/CaM Kinase III −6.0230 Ranolazine dihydrochloride −2.104 1.7711E−02 no Lipid Inhibitor pFOX −8.2305 Rolipram −2.091 1.8254E−02 no Cyclic Nucleotides Inhibitor PDE IV −5.1219 Phosphoramidon disodium −0.510 3.0512E−01 no Biochemistry Inhibitor Endopeptidase −20.5364 Rosco

ne 0.003 4.9891E−01 no Phosphorylation Inhibitor CDK −0.0626 Ro 8-4304 −2.168 1.4331E−02 no Glutamate Antagonist NMDA-NR2B −3.3769 RX 821022 hydrochloride 0.249 4.0167E−01 no Adrenoceptor Antagonist alpha2 −5.5331 Ribavirin −1.194 1.1620E−01 no Cell Cycle Inhibitor IMP dehydrogenase −5.4344 Ranitidine hydrochloride 0.023 4.9093E−01 no Histamine Antagonist H2 −8.8616 Ritanserin −0.695 2.4332E−01 no Serotonin Antagonist 5-HT2/5-HT1C −7.7433 R

 hydrochloride −1.747 4.0255E−02 no Adrenoceptor Antagonist alpha2 −2.0332 Ro 15-6401 hydrochloride −2.181 1.4690E−02 no Neurotransmission Inhibitor MAO-B −1.0523 Ro 41-1049 hydrochloride 1.328 9.2137E−02 no Neurotransmission Inhibitor MAO-A −4.7684 Ro 41-0950 −0.360 3.5942E−01 no Neurotransmission Inhibitor CDMT −7.6263 Reactive Blue 2 2.003 2.2573E−02 no P2 Receptor Antagonist P2Y −10.1270 Riluzole −1.033 1.5090E−01 no Glutamate Antagonist Release −1.7431 Risperidone 1.594 4.5097E−02 no Dopamine Antagonist DRD2 −10.2931 Rilmenidine hemifumarate 0.520 2.9920E−01 no Imidazoline Agonist I1 −5.7097 Ro 04-6790 dihydrochloride 0.343 3.

7E−01 no Serotonin Antagonist 5-HT6 −5.2757 (±)-Sol

 hydrochloride −0.813 2.0811E−01 no Adrenoceptor Antagonist beta −4.9715 SB-366791 −1.419 7.7915E−02 no Vanilloid Antagonist VR1 −3.0158 Sodium nitroprusside dihydrate 2.404 8.1010E−03 no Nitric Oxide Releaser −1.0698 (±)-Synephnne −0.149 4.4085E−01 no Adrenoceptor Agonist alpha −5.2875 Sulfaphenazole −1.362 8.6671E−02 no Multi-Drug Resistance Inhibitor Cytochrome P4502O −9.1951 Seglitide −0.662 2.5398E−01 no Somatostatin Agonist sst2 −18.2993 Sulindac sulfone 0.592 2.7080E−01 no Prostaglandin Inhibitor −7.3445 Cortexclone maleate −1.434 7.5772E−02 no Dopamine Antagonist DRD2 −14.1896 SR 57227A −1.400 8.0740E−02 no Serotonin Agonist 5-HT3 −7.7427 (−)-Scopolamine hydrobromide −0.742 2.2919E−01 no Cholinergic Antagonist Muscarinic −10.2442 SC-560 1.113 1.2257E−01 no Prostaglandin Inhibitor COX-1 −4.6793 Semicarbazide hydrochloride −1.405 8.0029E−02 no Neurotransmission Inhibitor MAO −6.0341 (−)-Scopolamine methyl nitrate −0.451 3.2

E−01 no Cholinergic Antagonist Muscarinic −18.9174 DL-Stearoylcamitine chloride 0.638 2.0181E−01 no Phosphorylation Inhibitor PKC −2.3326 Spermidine trihydrochloride 1.259 1.0418E−01 no Glutamate Ligand NMDA-Polyamine −4.9703 SNC80 −0.457 3.2368E−01 no Opioid Agonist delta −4.2921 SKF 83959 hydrobromide −1.357 8.7380E−02 no Dopamine Agonist D1 −10.4451 Spermine tetrahydrochloride 0.394 3.4672E−01 no Glutamate Antagonist NMDA-Polyamine −3.3021 SKF 75670 hydrobromide −0.142 4.4350E−01 no Dopamine Agonist D1 −6.1094 SO 12220 −1.640 5.0479E−02 no Prostaglandin Antagonist EP1 −1.9074 SKF 89826 −0.044 4.8258E−01 no Dopamine Agonist D1 −10.7223 SKF 23555 hydrobromide 0.789 2.1492E−01 no Dopamine Agonist D1 −7.5982 N-Oleoyldopamine 0.483 3.2158E−01 no Neurotransmission Ligand CB1 −9.5690 Spironolactone −0.526 2.9958E−01 no Hormone Antagonist Mineralocorticoid −7.4931 SCH-202678 hydrobromide 0.360 3.5948E−01 no G protein Modulator GPCR −3.7669 D-Serine −0.143 4.4320E−01 no Glutamate Agonist NMDA-Glycine −4.1465 Albutanol hemisulfate −0.949 1.7130E−01 no Adrenoceptor Agonist beta2 −7.1289 N-Succinyl-L-proline 0.725 2.3438E−01 no Neurotransmission Inhibitor ACE −5.6487 Acetamide −1.940 2.6178E−02 no Biochemistry Inhibitor Carbonic anhydrase −2.0047 N-(4-Aminobutyl)-5-chloro-2-naphthalenesulfonamide −0.923 1.7604E−01 no Intracellular Calcium Antagonist Calmodulin −1.6370 L-azetidine-2-carboxylic acid 0.984 1.6263E−01 no Biochemistry Inhibitor Collagen −3.9090 p-Aminoclonidine hydrochloride −0.048 4.8095E−01 no Adrenoceptor Agonist alpha2 −8.3850 3-aminobenzamide −1.034 1.6048E−01 no Apoptosis Inhibitor PARS −4.4935 (±)-Norepinephrine (+)bitartrate 0.099 4.6055E−01 no Adrenoceptor Agonist −10.1650 4-Amino-1,5-naphthalimide 1.875 3.0420E−02 no Apoptosis Inhibitor PARP −1.0499 (±)-alpha-Lipoic Acid 0.342 3.6624E−01 no Cell Stress Coenzyme Pyruvate dehydrogenase −1.9717 DL-Thiorphan −0.312 3.7768E−01 no Neurotransmission Inhibitor Enkephainase −6.4858 Tolbutanol hydrochloride −1.767 3.8835E−02 no Adrenoceptor Agonist beta −6.3849 Tyrphostin AG 34 −2.319 1.0192E−02 no Phosphorylation Inhibitor Tyrosine kinase −12.9224 Triamcinclone −0.184 4.2701E−01 no Hormone Agonist Glucocorticoid −7.5110 S(−)-Ti

 maleate −0.767 2.2140E−01 no Adrenoceptor Antagonist beta −14.6252 Tripro

 hydrochloride −0.406 3.4234E−01 no Histamine Antagonist HRH1 −3.7367 Tyrphostin AG 112 0.333 3.6947E−01 no Phosphorylation Inhibitor Tyrosine kinase −9.5119 Tyrphostin 1 −0.642 2.0031E−01 no Phosphorylation Inhibitor EGFR −9.6061 Tyrphostin 23 −0.840 2.0058E−01 no Phosphorylation Inhibitor EGFR −17.6797 TFPI hydrochloride −1.158 1.2388E−01 no Nitric Oxide Inhibitor nNOS −1.7477 Na-p-Tosyl-L-lysine chloromethyl ketone hydrochloride 0.005 4.9808E−01 no Cyclic Nucleotides Inhibitor Adenylyl cyclase −9.0926 Tyrphostin 25 −0.259 3.9777E−01 no Phosphorylation Inhibitor EGFR −14.8744 1-[2-(Trifluoromethyl)phenyl]imidazole −0.158 4.3738E−01 no Nitric Oxide Inhibitor NOS −6.3332 SU 4312 0.269 3.9392E−01 no Phosphorylation Inhibitor KDR −8.4051 SR 59230A oxalate −1.222 1.1095E−01 no Adrenoceptor Antagonist beta3 −11.1051 SKF 89976A hydrochloride −0.2333 4.0797E−01 no GABA Inhibitor GAT-1 −0.1813 SIB 1757 −1.752 3.9859E−02 no Glutamate Antagonist mGluR5 −8.2872 SIB 1893 −0.848 1.9822E−01 no Glutamate Antagonist mGluR5 −4.4480 1-(1-Naphthyl)piperazine hydrochloride 0.230 4.0901E−01 no Serotonin Antagonist 5-HT2 −7.5485 1-(2-Methoxyphenyl)piperazine hydrochloride −0.639 2.6148E−01 no Serotonin Agonist 5-HT1 > 5-HT2 −9.6082 Spiroxatrine 0.172 4.5148E−01 no Serotonin Agonist 5-HT1A −7.0795 SR-95531 −0.957 1.5917E−01 no GABA Antagonist GABA-A −1.7649 (±)-6-Chloro-PB hydrobromide −2.267 1.1691E−02 no Dopamine Agonist D1 −10.5959 SKF 91488 dihydrochloride −0.765 2.2184E−01 no Histamine Inhibitor Histamine N-methyltransfe −4.4216 Suramin hexasodium 2.284 1.1174E−02 no P2 Receptor Antagonist P2X, P2Y −16.9942 SQ 22536 0.562 2.8721E−01 no Cyclic Nucleotides Inhibitor Adenylyl cyclase −4.4435 Sepiapterin 1.795 3.6295E−02 no Nitric Oxide Cofactor NOS −8.8178 R(−)-SCH-12579 maleate 1.009 5.3785E−02 no Dopamine Antagonist D1 −1.3407 (±)-SKF 38393, N-allyl-, hydrobromide −1.590 5.1986E−02 no Dopamine Agonist D1 −2.9637 SB 206563 hydrochloride −1.365 8.0107E−02 no Serotonin Antagonist 5-HT2C/5-HT2B −0.5886 L-Tryptophan 0.224 4.1134E−01 no Serotonin Precursor −17.6188 Tranilast 0.174 4.3108E−01 no Leukotriene Inhibitor LTC4 −6.2394 Taurine 0.533 2.9710E−01 no Glycine Agonist −2.4249 Tolbutamide −0.303 3.8037E−01 no Hormone Releaser Insulin −13.2463 Tetraethyl

 disulfide 2.347 9.4627E−03 no Biochemistry Inhibitor Alcohol Dehydrogenase −2.7989 Tetraisopropyl pyrophosphoramide −1.114 1.3262E−01 no Biochemistry Inhibitor Butylcholinesterase −3.4763 Tetraminole hydrochloride 2.649 4.0391E−03 no Phosphorylation Inhibitor Phosphatase −9.6745 Trihexylphenidyl hydrochloride 1.215 1.1219E−01 no Cholinergic Antagonist Muscarinic −3.5988 Theopryiine 0.370 3.5573E−01 no Adenosine Antagonist A1 > A2 −11.3611 (E)-4-amino-2-butenoic acid −2.149 1.5824E−02 no GABA Agonist GABA-C −5.0086 Tetradecylthioacetic acid −0.324 3.7300E−01 no Transcription Agonist PPAR-alpha −5.5493 Trequinsin hydrochloride −0.971 1.6581E−01 no Cyclic Nucleotides Inhibitor PDE III −4.8392 Tyrphostin AG 879 −1.607 5.4042E−02 no Phosphorylation Inhibitor TrkA −11.2234 Tetraethylammonium chloride 0.123 4.5107E−01 no Cholinergic Antagonist Nicotinic −0.9450 Tolazamide 1.431 7.6219E−02 no Hormone Releaser Insulin −13.2030 Terbutaline hemisulfate 0.641 2.6079E−01 no Adrenoceptor Agonist beta −8.9156 4-Hydroxyphenethylamine hydrochloride 1.030 1.5154E−01 no Dopamine Agonist −2.6218 Tri

pramine maleate 0.568 2.8512E−01 no Serotonin Inhibitor Reuptake −5.4862 Tyrphostin AG 490 1.802 3.5809E−02 no Phosphorylation Inhibitor JAK2 −17.3461 TTNPB −2.158 1.5472E−02 no Transcription Ligand RAR-alpha, beta gamma −6.5131 Tetrahydrozoline hydrochloride −0.469 3.1944E−01 no Adrenoceptor Agonist alpha −6.7607 Tyrphostin AG 494 −2.275 1.1443E−02 no Phosphorylation Inhibitor EGFR −18.5744 N-p-Tosyl-L-phenylalanine chloromethyl ketone 0.337 3.6819E−01 no Biochemistry Inhibitor Chymotryprin alpha −6.2244 (6R)-5,6,7,8-Tetrahydro-L-bioptenin hydrochloride 0.976 1.6460E−01 no Neurotransmission Cofactor Tyrosine −10.0438 Tyrphostin AG 527 −1.607 5.3975E−02 no Phosphorylation Inhibitor EGFR −20.3183 Theobromine −1.392 8.1993E−02 no Adenosine Antagonist A1 > A2 −8.7094 (±)-Taxifolin 1.321 9.3301E−02 no Cell Stress Inhibitor Antioxidant −12.8430 Tyrphostin AG 528 −0.148 4.4112E−01 no Phosphorylation Inhibitor EGFR −13.4954 Terazosin hydrochloride −0.057 4.7710E−01 no Adrenoceptor Antagonist alpha1 −1.6037 Tyrphostin AG 537 −1.249 1.0588E−01 no Phosphorylation Inhibitor EGFR −20.6782 Tyrphostin AG 555 −0.681 2.4787E−01 no Phosphorylation Inhibitor EGFR −20.1332 Tyrphostin AG 698 1.510 6.5584E−02 no Phosphorylation Inhibitor EGFR −21.0985 Tyrphostin AG 809 −1.315 9.4172E−02 no Phosphorylation Inhibitor Tyrosine kinase −25.9684 Thio-NADP sodium 0.366 3.5715E−01 no Intracellular Calcium Blocker NAADP-induced −12.7713 Tyrphostin AG 535 2.230 1.2874E−02 no Phosphorylation Inhibitor Tyrosine kinase −20.3183 Amantadine hydrochloride −0.653 2.5694E−01 no Dopamine Releaser −3.1592 Aminophyline ethylenediamine −1.537 6.2140E−02 no Adenosine Antagonist A1/A2 −15.7095 S-(p-Azidophenacyl)glutathione −0.003 4.9890E−01 no Multi-Drug Resistance Modulator Glutathione S-transferase −10.4568 N-Acetyl-5-hydroxytryptamine −1.060 1.4447E−01 no Melatonin Precursor −21.5479 Amintricarboxylic acid 0.571 2.8403E−01 no Apoptosis Inhibitor Topoil −7.1275 (±)-2-Amino-4-phosphonobutyric acid 1.893 2.9164E−02 no Glutamate Antagonist NMDA −4.4713 N-arachidonylglycine 0.387 3.4935E−01 no Cannabinoid Inhibitor FAAH −4.2606 WIN 62,577 2.351 9.3727E−03 no Tachyldinin Antagonist NK1 −17.1837 S(−)-Willardiine 1.251 1.0641E−01 no Glutamate Agonist AMPActinase −7.1410 WAY-100635 maleate −0.497 3.0976E−01 no Serotonin Antagonist 5-HT1A −14.1470 S-5-lodowillardiine −0.355 3.6125E−01 no Glutamate Agonist AMPA −6.9856 Xylacine hydrochloride 0.375 3.5365E−01 no Adrenoceptor Agonist alpha2 −8.1210 Xancterol hemi

ate −0.124 4.5053E−01 no Adrenoceptor Agonist beta1 −15.3573 Xyl

 hydrochloride 0.296 3.8361E−01 no Adrenoceptor Agonist alpha −1.2434 Xanthine amine congener 0.001 4.9954E−01 no Adenosine Antagonist A1 −24.1320 Yohimbine hydrochloride −1.655 4.8820E−02 no Adrenoceptor Antagonist alpha2 −2.0332 YC-1 0.433 3.3233E−01 no Cyclic Nucleotides Activator Guanylyl cyclase −10.1318 Zonicamide sodium −0.917 1.7959E−01 no Anticonvulsant −8.1550 Zardavarine −0.341 3.6646E−01 no Cyclic Nucleotides Inhibitor PDE III/PDE IV −5.7003 Zimedine dihydrochloride −0.649 2.5817E−01 no Serotonin Inhibitor Reuptake −4.1985 Tetracaine hydrochloride −0.020 4.9221E−01 no Na+ Channel Modulator −1.2589 Tyrphostin 47 0.178 4.2258E−01 no Phosphorylation Inhibitor EGFR −19.4361 Tyrphostin 51 −0.918 1.7939E−01 no Phosphorylation Inhibitor EGFR −10.5293 T-1032 −2.020 2.1672E−02 no Cyclic Nucleotides Inhibitor PDE V −5.7604 I-OMe-Tyrphostin AG 539 −0.737 2.3059E−01 no Phosphorylation Inhibitor IGF-1 RTK −15.0767 Tyrphostin AG 538 −0.395 3.4624E−01 no Phosphorylation Inhibitor IGF-1 RTK −19.5274 Trimethoprim −1.230 1.0840E−01 no Antibiotic Inhibitor Dihydrofolate inductase −2.7962 T

tine 0.167 4.3359E−01 no Adrenoceptor Inhibitor Reuptake −10.8802 T-

0.077 4.6928E−01 no Cyclic Nucleotides Inhibitor PDE V −10.0449 D-609 potassium −0.896 1.8503E−01 no Lipid Inhibitor PIPLC −6.4571 Tyrphostin AG 126 −0.410 3.4082E−01 no Phosphorylation Inhibitor TNFalpha −16.9960 Terfenadine 0.755 2.2503E−01 no Histamine Antagonist HRH1 −3.2974 Tropicamide 0.823 2.0533E−01 no Cholinergic Antagonist M4 −15.2981 THIP hydrochloride 0.361 3.5894E−01 no GABA Agonist GABA-A −6.8890 Trifluperidol hydrochloride −1.621 5.2465E−02 no Dopamine Antagonist D1/D2 −5.7072 3-Tropanyl-indole-3-carboxylate hydrochloride −1.528 6.2309E−02 no Serotonin Antagonist 5-HT3 −5.4495 Tracazolate −0.315 3.7833E−01 no GABA Modulator −10.9470 3-Tropanylindole-3-carboxylate methiodide −0.344 3.

E−01 no Serotonin Antagonist 5-HT3 −15.6039 Telenzepine dihydrochloride 0.381 3.5148E−01 no Cholinergic Antagonist M1 −3.9471 Thioperamide maleate −0.154 4.3894E−01 no Histamine Antagonist H3 −18.2020 (±)-Thalidomide 0.521 3.0117E−01 no Cyto skeleton and ECM Inhibitor TNFalpha −5.6805 R(+)-Terguride −2.004 2.2512E−02 no Dopamine Agonist −15.7008 Thiocitrulline −0.147 4.4139E−01 no Nitric Oxide Inhibitor nNOS, eNOS −7.7510 Tyrphostin A9 −1.746 4.0382E−02 no Phosphorylation Inhibitor PDGFR −9.9304 TPMPA 0.874 1.9101E−01 no GABA Antagonist GABA-C −5.8605 U-75302 −0.172 4.3103E−01 no Leukotriene Agonist BLT1 −8.3553 Uridine 5′-diphosphate sodium 0.707 2.3200E−01 no P2 Receptor Agonist P2Y −7.6702 U-73122 −1.194 1.1617E−01 no Lipid Inhibitor PLC, A2 −15.5197 SKF 95282 dimaleate 0.424 3.3576E−01 no Histamine Antagonist H2 −2.9694 4-Imidazoleacrylic acid −0.264 3.9608E−01 no Histamine Inhibitor Histidine ammonia-lyase/ −12.7023 Urapidil hydrochloride 0.157 4.3754E−01 no Adrenoceptor Antagonist alpha1 −8.1990 Urapidil, 5-Meethly- −0.783 2.1677E−01 no Adrenoceptor Antagonist alpha1A −7.7682 U-69593 −0.728 2.3336E−01 no Opioid Agonist kappa −1.0973 UK 14,304 −0.210 4.1672E−01 no Adrenoceptor Agonist alpha2 −7.3309 U-101958 maleate −2.065 1.9472E−02 no Dopamine Antagonist D4 −4.7843 U0126 0.711 2.3855E−01 no Phosphorylation Inhibitor MEK1/MEK2 −7.7131 (±)-Verapamil hydrochloride 1.008 1.5500E−01 no Ca2+ Channel Modulator L-type −1.4780 VUF 5574 0.581 2.8357E−01 no Adenosine Antagonist A3 −7.2944 Vinpocetine 0.433 3.3256E−01 no Cyclic Nucleotides Inhibitor PDE 1 −0.0438 Vancomycin hydrochloride from Streptomyces orientalis −0.064 4.7408E−01 no Antibiotic Cell wall synthesis −0.4820 (±)-gamma-Vinyl GABA −0.701 2.4100E−01 no GABA Inhibitor Transaminase −1.7994 (±)-V

 hydrochloride −1.267 2.4663E−02 no Cholinergic Inhibitor ACh storage −4.9330 Wort

 from Penicillium funicolosum 0.408 3.4189E−01 no Phosphorylation Inhibitor PTZK −8.7892 1400W dihydrochloride −0.275 3.9178E−01 no Nitric Oxide Inhibitor NOS −2.6662 WS 04 −1.683 4.6161E−02 no Cholinergic Ligand M2 −4.4336 (R)-(+)-WIN 55,212-2 methylate −0.681 2.4803E−01 no Cannabinoid Agonist −1.2169 GABA −0.439 3.3035E−01 no GABA Agonist −2.7784 Acetyl-beta-methylcholine chloride −0.338 3.6762E−01 no Cholinergic Agonist M1 −1.7344 5-azacytidine −1.398 8.1104E−02 no DNA Metabolism Inhibitor DNA methyltransferase −1.7173 5-(N-Ethyl-N-isopropyl)amiloride −0.289 3.8846E−01 no Ion Pump Blocker Na+/H+ Antiporter −11.6381 3-Aminopropionitrile fumarate 1.234 1.0853E−01 no Multi-Drug Resistance Substrate CYP450 −2.0810 Apipenin 1.824 3.4069E−02 no Cell Cycle Inhibitor −7.0447 Gabaculine hydrochloride −2.256 1.2023E−02 no GABA Inhibitor GABA transaminase −5.5637 AA-861 1.517 6.4828E−02 no Leukotriene Inhibitor 5-lipoxygenase −3.1329 9-Amino-1,2,3,4-tetrahydroacridine hydrochloride −1.021 1.5361E−01 no Cholinergic Inhibitor Cholinesterase −1.2209 AL-8610 −1.806 3.5496E−02 no Prostaglandin Antagonist FP Receptor −1.0281 1-Aminobenzotriazole 0.524 3.0028E−01 no Multi-Drug Resistance Inhibitor CYP450, chloroperoxidase −3.6565 O-(Carboxymethyl)hydroxylamine hemihydrochloride −2.058 1.9775E−02 no Biochemistry Inhibitor Aminotransferase −2.5668 5-(N,N-Dimethyl)

ride hydrochloride 2.396 8.2873E−03 no Ion Pump Blocker Na+/H+ Antiporter −10.6869 Amiprilose hydrochloride −0.778 2.1821E−01 no Immune System Modulator −3.5961 Sandoz 58-035 0.332 3.6977E−01 no Lipid Inhibitor ACAT −7.3180 (±)-2-Amino-3-phosphonopropionic acid 1.258 1.0569E−01 no Glutamate Antagonist NMDA −3.8618 L-Arginine 0.559 2.8802E−01 no Nitric Oxide Precursor −3.9612 (±)-2-Amino-7-phospheneheptanoic acid −1.020 1.5391E−01 no Glutamate Antagonist NMDA −4.2353 (±)-2-Amino-5-phosphonopentanoic acid −1.045 1.4797E−01 no Glutamate Antagonist NMDA −4.3519 L-732,139 0.503 3.0758E−01 no Tachykinin Antagonist NK1 > NK2, NK3 −13.3105 Acetylsalicyclic acid −0.481 3.1520E−01 no Prostaglandin Inhibitor COX-3 > COX-1 > COX-2 −4.6918 5-(N-Methyl-N-isobutyl)amiloride 1.571 3.0554E−02 no Ion Pump Blocker Na+/H+ Antiporter −11.0245 Acetylthiocholine chloride 0.004 4.0822E−01 no Cholinergic Agonist Nicotinic −4.7778 4-Androsten-4-ol-3,17-dione 0.194 4.2293E−01 no Hormone Inhibitor Aromatase −14.6147 2-(2-Aminoethyl)isothiourea dihydrobromide −1.251 1.0541E−01 no Nitric Oxide Inhibitor NOS −2.0427 cis-Azetidine-2,4-dicarboxylic acid −2.251 1.2198E−02 no Glutamate Modulator NMDA −3.5649 trans-Azetidine-2,4-dicarboxylic acid −0.349 3.6350E−01 no Glutamate Agonist mGluR1, mGluR5 −3.5649 AGN 192402 hydrochloride 0.703 2.4098E−01 no Imidazoline Ligand I1 −4.7455 AIDA 0.154 4.3880E−01 no Glutamate Antagonist mGluR1 −7.5362 A-77038 hydrochloride 1.440 7.4902E−02 no Dopamine Agonist D1 −5.7849 ATPA 0.283 3.8853E−01 no Glutamate Agonist Exinate −10.2981 ARL 07156 trisodium salt −0.168 4.3329E−01 no P2 Receptor Inhibitor

-ATPase −9.5979 Bectomethasone 0.267 3.9475E−01 no Hormone Glucocorticoid −9.5218 2,3-Butanedione monoxime −1.810 3.5125E−02 no K+ Channel Blocker ATP-sensitive −3.0410 SB 222200 −1.695 4.5077E−02 no Tachykinin Antagonist NH3 −0.3519 1-benzoyl-5-methoxy-2-methylindole-3-acetic acid −0.955 1.8978E−01 no Multi-Drug Resistance Inhibitor MRP1 −1.2294 p-Benzoquinone −1.571 5.8049E−02 no DNA Repair Inhibitor G:C site −1.6650 B-Bromo-cGMP sodium −1.005 1.5751E−01 no Cyclic Nucleotides Activator −12.4831 Bromoenol lactone 0.248 4.0190E−01 no Lipid Inhibitor PLA2 −2.8194 Benzamide 0.550 2.9122E−01 no Apoptosis Inhibitor PARS −2.8316 N-Acetyl-L-Cysteine −1.821 5.2499E−02 no Glutamate Antagonist −4.6648 N-Acetyltryptamine 1.020 1.5384E−01 no Melatonin Agonist-An −17.6180 (±)-Atenolol −0.558 2.5518E−01 no Adrenoceptor Antagonist beta1 −14.7808 5alpha-Androstane-3alpha,17beta-diol −0.381 3.5158E−01 no Hormone Metabolite Androgen −15.2440 L-allylglycine −1.155 1.2402E−01 no Biochemistry Inhibitor −3.9370 H-9 dihydrochloride −0.190 4.2469E−01 no Phosphorylation Inhibitor cAMP- and cGMP-dependent −10.7677 6-Aminohexanoic acid −2.179 1.4649E−02 no Immune System Inhibitor Blood Clotting −3.2682 ATPC −1.

4.8478E−02 no Glutamate Antagonist GluR1-4 −9.5487 Allop

0.147 4.4145E−01 no Cell Stress Inhibitor Xanthine oxidase −6.5941 Amiodarone hydrochloride 0.929 1.7639E−01 no Adrenoceptor Agonist alpha/beta −0.5073 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride 0.363 3.5814E−01 no Biochemistry Inhibitor Serine Protease −6.0757 Alprenolol hydrochloride −2.143 1.8057E−02 no Adrenoceptor Antagonist beta −15.2992 Altretamine −1.322 9.3085E−02 no DNA Metabolism Inhibitor −1.0683 N-Acetyldopamine monohydrate 0.467 3.2034E−01 no Dopamine Precursor −11.2009 Aminoquanidine hydrochloride −0.001 4.9971E−01 no Nitric Oxide Inhibitor NOS −2.9994 BW 284c51 −0.402 3.4398E−01 no Cholinergic Inhibitor Acetylcholinesterase −4.8061 Adenosine −0.209 4.1740E−01 no Adenosine Agonist −2.9711 L-Aspartic acid 0.163 4.3519E−01 no Glutamate Agonist −3.3129 N-(4-Amino-2-chlorophenyl)ph

mide −0.602 2.7356E−01 no Anticonvulsant −4.4471 Adenosine 3′,5′-cyclic monophosphate −1.188 1.1734E−01 no Phosphorylation Activator PKA −7.9942 L(−)-Norepinephrine bitartrate −1.418 7.8127E−02 no Adrenoceptor Agonist alpha, beta1 −10.1859 5-(N,N-hexamethylene)amiloride 0.039 4.8462E−01 no Ion Pump Inhibitor Na+/H+ Antiporter −13.0180 4-Androstene-3,17-dione −0.692 2.4458E−01 no Hormone Precursor Androgen −13.1513 (±)-p-Aminoglutethimide −0.444 3.2849E−01 no Biochemistry Inhibitor P450-dependendent hydroxy −3.6754 (±)-HA-956 1.157 1.2368E−01 no Glutamate Antagonist NMDA-glycine −4.5024 Androsterone 1.947 2.5753E−02 no Hormone Androgen −17.5390 Antozoline hydrochloride 0.485 3.1371E−01 no Imidazoline Agonist −4.1995 Aniracetam −1.355 8.7788E−02 no Glutamate Agonist AMPA −8.1020 1,3-Diethyl-8-phenylxanthine 2.005 2.2458E−02 no Adenosine Antagonist A1 −20.0

8-(p-Sulfophenyltheophyline 1.047 1.4759E−01 no Adenosine Antagonist A1 > A2 −19.

1,3-Diphenyl-8-p-sulfophenylxanthine 4.743 1.0548E−06 no Adenosine Antagonist A1 > A2 −22.1458 2-Meth

 triphosphate tetrasodium −0.776 2.1877E−01 no P2 Receptor Agonist P2Y −0.6760 Adenosine amine congener −0.334 3.8901E−01 no Adenosine Agonist A1 −4.4147 Amoxapine −1.041 1.4885E−01 no Adrenoceptor Inhibitor Uptake −6.0297 R(+)-Atenolol 3.764 8.3501E−05 no Adrenoceptor Antagonist beta1 −14.7803 S(−)-Atenolol 0.617 2.6861E−01 no Adrenoceptor Antagonist beta1 −14.7803 1-Actyl-3,7-dimethyl-8-p-sulfophenylxanthine −2.178 1.4691E−02 no Adenosine Antagonist A2 −13.2451 trans-(±)-ACPD 0.315 3.7642E−01 no Glutamate Agonist Metabotropic −2.0313 1-Amino-1-cyclohexanecarboxylic acid hydrochloride −0.749 2.2678E−01 no Neurotransmission Substrate −1.302

Alaproslate hydrochloride −0.172 4.3153E−01 no Serotonin Inhibitor Reuptake −1.0488 Rp-cAMPS triethylamine 1.186 1.1788E−01 no Phosphorylation Inhibitor PKA −12.7973 SB 200

 hydrochloride 2.437 7.3995E−03 no Serotonin Antagonist 5-HT2C/2B −11.7331 D(−)-2-Amino-7-phosphonoheptanoic acid 0.985 1.8220E−01 no Glutamate Antagonist NMDA −4.2353 Acetohexamide −2.240 1.2547E−02 no Harmone Releaser Insulin −12.1480 SKF 97541 hydrochloride −0.736 2.3101E−01 no GABA Agonist GABA-B −3.2485 cis-4-Aminocrotonic acid −1.088 1.3845E−01 no GABA Agonist GABA-C −5.0086 N6-2-(4-Aminophenyl)ethyladenosine −1.323 9.3244E−02 no Adenosine Agonist A3 −7.3150 Agroclavine −0.911 1.8118E−01 no Dopamine Agonist −10.9883 gamma-Acetylinic GABA 1.285 9.9459E−02 no GABA Inhibitor GABA transaminase −2.0503 AB-MECA 0.760 2.2351E−01 no Adenosine Agonist A3 −6.1580 Alloxazine −0.442 3.29

E−01 no Adenosine Antagonist A2b −5.0147 CGP-7930 −0.411 3.4052E−01 no GABA Modulator GABA-B −2.6898 CGP-13501 −1.096 1.3653E−01 no GABA Modulator GABA-B −2.8414 CP55940 1.396 8.1367E−02 no Cannabinoid Agonist −6.5601 L-Cycloserine −0.155 4.3834E−01 no Sphingolipid Inhibitor Ketosphinganine synthetas −5.7186 (+)-Cateonin Hydrate 0.511 3.0484E−01 no Cell Stress Inhibitor Antioxidant −11.1574 Chlorpropamide −0.190 4.2463E−01 no Hormone Releaser Insulin −9.0400 1-(4-Chlorobenzyl)-5-methoxy-2-methylindole-3-acetic acid −1.584 5.8573E−02 no Multi-Drug Resistance Inhibitor MRP1 −9.0898 Choline bromide −0.730 2.3268E−01 no Cholinergic Substrate Choline acetyltransferase −2.6283 Ceramide −0.827 2.0421E−01 no Phosphorylation Inhibitor Diacylglycerol kinase −0.7919 CB 1954 −1.070 1.4227E−01 no DNA Intercalator −7.7981 Carcinine dihydrochloride −1.023 1.5311E−01 no Cell Stress Inhibitor Antioxidant −10.2686 Corticosterone −2.285 1.1148E−02 no Hormone Glucocorticoid −8.9885 Cortisone −0.581 2.8073E−01 no Hormone Corticosteroid −8.5526 3-Bromo-7-nitroindazole −1.680 4.6484E−02 no Nitric Oxide Inhibitor NOS −9.6580 (+)-Bromopeptine methanesulfonate 0.028 4.8886E−01 no Dopamine Agonist DRD2 −21.8304 O6-benzylguanine −1.177 1.1967E−01 no DNA Repair Inhibitor −6.8215 N-Bromoacetamide −1.362 8.8669E−02 no Na+ Channel Modulator −1.7090 Benzamil hydrochloride −1.054 1.4591E−01 no Ion Pump Blocker Na+/H+, Na+/Ca2+ Pump −5.3837 L-Buthionine-sulfoximine 0.513 3.0333E−01 no Multi-Drug Resistance Inhibitor −5.7085 DL-Buthionine-[S.P.]-sulfoximine −1.022 1.5341E−01 no Multi-Drug Resistance Inhibitor −5.7085 Bumetanide −2.182 1.4545E−02 no Ion Pump Inhibitor Na+-K+-2Cl− cotransporter −5.3951 Betaine aldehyde chloride −0.070 4.7207E−01 no Cholinergic Metabolite Choline dehydrogenase −2.4729 Benazoline oxalate −0.335 3.8890E−01 no Imidazoline Agonist I2 −5.9911 BWB70C −0.893 1.8586E−01 no Leukotriene Inhibitor 5-lipoxygenase −2.7024 5-Bromo-2′-deoxyuridine 2.580 4.9400E−03 no DNA Metabolism Inhibitor −3.6110 (±)-Baclofen −1.069 1.4250E−01 no GABA Agonist GABA-B −7.7439 SB 202193 −1.124 1.3042E−01 no Phosphorylation Inhibitor p38 MAPK −8.6028 Bay 11-7085 2.180 1.4646E−02 no Cell Cycle Inhibitor lkB-alpha −8.0406 Beta

 hydrochloride 0.984 1.

E−01 no Adrenoceptor Antagonist beta1 −14.7478 Betamethasone 0.881 1.8913E−01 no Hormone Glucocorticoid −9.5218 Buspirone hydrochloride −1.775 3.7910E−02 no Serotonin Agonist 5-HT1A −8.0068 Benserazide hydrochloride 0.007 4.9702E−01 no Biochemistry Inhibitor Decarboxylase −7.5822 Budesonide −1.994 2.3069E−02 no Hormone Cortisol −4.0628 8-Bromo-cAMP sodium 2.309 1.0469E−02 no Cyclic Nucleotides Activator −13.0857 Ro 20-1724 0.587 2.7848E−01 no Cyclic Nucleotides Inhibitor cAMP phosphodiesterase −4.4839 Bestatin hydrochloride 0.643 2.

E−01 no Biochemistry Inhibitor Aminopeptidase −6.8215 Bretylium tosylate −0.002 4.

E−01 no Adrenoceptor Blocker −8.8373 BP 897 −1.715 4.3173E−02 no Dopamine Agonist D3 −6.2599 (E)-5-(2-Bromovinyl)-2′-deoxyuridine −2.123 1.0503E−02 no Immune System Inhibitor HSV1 −2.5745 Chloroethyl

ine dihydrochloride 0.861 1.9473E−01 no Adrenoceptor Antagonist alpha1B −7.8626 6-Fluoronorepinephrine hydrochloride −1.168 1.2140E−01 no Adrenoceptor Agonist alpha −6.6614 Bromoacetyl

 menthane 1.442 7.4623E−02 no Adrenoceptor Antagonist beta −14.5755 Benoxathian hydrochloride 0.265 3.9540E−01 no Adrenoceptor Antagonist alpha1 −7.3187 Phenoxybenzamine hydrochloride −1.512 6.5240E−02 no Adrenoceptor Blocker alpha −2.5903 Bupropion hydrochloride 0.267 3.9469E−01 no Dopamine Blocker Reuptake −3.1372 (±)-Bay K 8644 0.853 1.9691E−01 no Ca2+ Channel Agonist L-type −9.8317 Bromoacetylcholine bromide −0.355 3.6139E−01 no Cholinergic Ligand −4.7430 BMY 7378 dihydrochloride −0.659 2.5500E−01 no Serotonin Agonist 5-HT1A −8.6878 R(+)-6-Bromo-APB hydrobromide 1.532 6.2732E−02 no Dopamine Agonist D1/D5 −6.4948 N2-Benzyl-5′-N-ethylcarboxamidoadenosine −0.798 2.1254E−01 no Adenosine Agonist A3 −4.0973 BU224 hydrochloride 0.404 3.4294E−01 no Imidazoline Antagonist I2 −6.8354 B-HT 933 dihydrochloride −1.280 1.0022E−01 no Adrenoceptor Agonist alpha2 −0.5572 BRL 37344 sodium −1.725 4.2299E−02 no Adrenoceptor Agonist beta3 −6.1685 BRL 54443 maleate 0.338 3.8775E−01 no Serotonin Agonist 5-HT1E/1F −17.4858 BW 723C86 0.725 2.3431E−01 no Serotonin Agonist 5-HT2B −17.1873 Citicoline sodium −0.133 4.4704E−01 no Lipid Inhibitor PLA2 −1.5578 Ciprofibrate −1.328 9.2430E−02 no Transcription Ligand PPAR-alpha −7.0194 6-Chloromelatonin −1.659 4.8549E−02 no Metatonin Agonist −18.1502 Carmustine 2.191 1.4231E−02 no DNA Intercalator −5.6758 PK t1195 −0.468 3.2005E−01 no GABA Antagonist Benzodiazepine −5.6993 Caffeic Acid 0.320 3.7452E−01 no Cell Stress Inhibitor Antioxidant −12.2125 Cilostazol 0.822 2.0558E−01 no Cyclic Nucleotides Inhibitor PDE III −6.1607 Caffeine 0.411 3.4041E−01 no Adenosine Inhibitor Phosphodiesterase −14.5759 Cyclophosphamide monohydrate −0.976 1.6459E−01 no DNA Intercalator −5.5771 Caffeic acid phenethyl ester 1.306 9.5730E−02 no Cell Cycle Inhibitor NFkB −11.5965 Cinoxacin −1.095 1.3684E−01 no Antibiotic Inhibitor −0.0911 Carisoprodol −1.795 3.6351E−02 no Neurotransmission Skeletal muscle −6.5522 Centrophenzaine hydrochloride −0.330 3.7061E−01 no Nootropic −0.6260 Clemasfine fumarate −2.023 2.1547E−02 no Histamine Antagonist HRH1 −5.4013 beta-Chloro-L-alanine hydrochloride −1.390 8.2254E−02 no Biochemistry Inhibitor Alanine aminotransferase −3.1222 Pyrocatechol −2.053 2.0033E−02 no Cell Cycle Inhibitor −2.1080 CPCCOEt −0.807 2.0990E−01 no Glutamate Antagonist mGluR1 −5.4393 L-Canaranine sulfate −0.902 1.8343E−01 no Nitric Oxide Inhibitor iNOS −6.4287 Cortisone Z1-acetate −2.218 1.3282E−02 no Hormone Cortisol −9.8430 Cyproterase acetate −1.803 3.5859E−02 no Hormone Antagonist Androgen −7.5603 DL-p-Chlorophenylalanine methyl ester hydrochloride 0.128 4.4922E−01 no Neurotransmission Inhibitor Tryptophan hydroxylase −3.4208 Cetasperin −0.186 4.2629E−01 no Phosphorylation Inhibitor Calcineurin phosphatase −6.2107 D-Cycloserine −1.240 1.0749E−01 no Glutamate Agonist NMDA-Glycine −5.7186 9-(4-Chlorophenylthic)-cAMP sodium 1.217 1.1188E−01 no Cyclic Nucleotides Activator −10.7572 Carbamazepine 1.114 1.3255E−01 no Anticonvulsant −6.5460 Captopril −1.285 9.9379E−02 no Neurotransmission Inhibitor ACE −6.0164 Carbachol −0.034 4.8851E−01 no Cholinergic Agonist −7.3897 Chlorzoxazone −1.495 6.7306E−02 no Nitric Oxide Inhibitor iNOS −2.0853 L-Cysteinesulfuric Acid 1.458 7.2457E−02 no Glutamate Ligand −4.0432 9-cyclopentyladenine 0.499 3.0996E−01 no Cyclic Nucleotides Inhibitor Adenylate cyclase −1.7579 Cimetidine 1.665 4.7022E−02 no Histamine Antagonist H2 −15.6553 Cyclobenzaprine hydrochloride 0.072 4.7138E−01 no Serotonin Antagonist 5-HT2 −0.3834 Clemizole hydrochloride 2.788 2.6501E−03 no Histamine Antagonist HRH1 −4.3715 2-Chloroadenosine −0.380 3.4004E−01 no Adenosine Agonist A1 > A2 −4.4821 Bethanechol chloride −0.549 2.5807E−01 no Cholinergic Agonist Muscarinic −3.3990 Cinnarizine −1.375 8.4610E−02 no Ca2+ Channel Blocker −2.7921 1-(3-Chlorophenyl)piperazine dihydrochloride 0.952 1.7066E−01 no Serotonin Agonist 5-HT1 −0.9409 SB 204741 −2.299 1.0744E−02 no Serotonin Antagonist 5-HT2B −10.7182 4-Chloromercuribenzoic acid −0.032 4.8726E−01 no Biochemistry Inhibitor −4.9331 (−)-Colinine −0.510 3.0507E−01 no Cholinergic Metabolite Nicofinic −0.2586 CL 316,243 0.521 2.6722E−01 no Adrenoceptor Agonist beta3 −9.7696 7-Chloro-4-hydroxy-2-phenyl-1,8-naphthyridine −0.401 3.4422E−01 no Adenosine Antagonist A1 −0.1894 Clotrimazole −0.715 2.3705E−01 no K+ Channel Inhibitor Ca2+-activated K+ channel −1.7128 CyprohopLactose hydrochloride 1.232 1.0898E−01 no Serotonin Antagonist 5-HT2 −5.8370 5-(N-Cyclopropyl)carboxamidoadenosine −1.701 4.4454E−02 no Adenosine Agonist A2 −0.6480 Calmetazole sodium 2.503 6.1504E−03 no Antibiotic Cell wall synthesis −3.7838 Clozapine 0.547 2.9208E−01 no Dopamine Antagonist D4 > D2, D3 −3.3166 (±)-p-Chlorophenylalanine −0.247 4.0241E−01 no Neurotransmission Inhibitor Tryptophan hydroxylase −4.5617 Clofibrate −1.738 4.1149E−02 no Lipid Modulator Lipoprotein lipase −4.1199 CB34 −1.081 1.3979E−01 no Benzodiozepine Ligand −5.9593 DL-Cycloserine −0.299 3.8263E−01 no Sphingc

pld Inhibitor Ketosphinganine synthase. −6.7185 McN-A-343 −0.089 4.6455E−01 no Cholinergic Agonist M1 −4.9137 Cystamine dihydrochloride 2.230 1.2874E−02 no Glutamate Inhibitor Transglutaminase −0.9088 Calcimycin 2.172 1.4942E−02 no Intracellular Calcium Ca2+ −11.3039 Cardharidin −0.578 2.8158E−01 no Phosphorylation Inhibitor PP2A −3.0587 Citalopram hydrobromide −1.859 3.1518E−02 no Serotonin Inhibitor Reuptake −4.9204 Clonicine hydrochloride 1.041 1.4898E−01 no Adrenoceptor Agonist alpha2 −8.6158 Clostamide 0.178 4.3029E−01 no Cyclic Nucleotides Inhibitor PDE III −7.2538 Cho

neric Acid 0.726 2.3390E−01 no Glutamate Inhibitor L-glutamic decarboxylate −5.4374 N6-Cycloproplyladenosine −0.784 2.1655E−01 no Adenosine Agonist A1 −3.3957 Cen

ridic Acid −0.553 2.9016E−01 no Phosphorylation Inhibitor PP1/PP2A −4.0610 Phenytoin sodium −0.217 4.1428E−01 no Anticonvulsant −7.1894 S(−)-Pindolol −0.965 1.8722E−01 no Adrenergic Antagonist beta −25.5497 (−)-alpha-Methylnorepinephrine 1.193 1.1634E−01 no Adrenoceptor Agonist −6.3305 Dilazep hydrochloride 0.245 4.0329E−01 no Adenosine Inhibitor Uptake −4.5746 1,7-Dimethylxanthine −0.882 2.5288E−01 no Adenosine Antagonist A1 > A2 −7.5630 Daphnefin −0.980 1.8359E−01 no Phosphorylation Inhibitor PK −7.3553 DM 235 −2.019 2.1731E−02 no Ncotropic −6.9228 5,5-Dimethyl-1-pyrroline-N-oxide −1.888 4.7874E−02 no Cell Stress Inhibitor Antioxidant −3.0181 Diacylglycerol Kinase Inhibitor II −1.390 8.2282E−02 no Phosphorylation Inhibitor Diacylglycerol kinase −3.7809 Dihydrexidine hydrochloride −0.415 3.3898E−01 no Dopamine Agonist D1 −5.3869 N-Methyldopamine hydrochloride −1.219 1.1143E−01 no Dopamine Agonist −11.1570 1,1-Dimethyl-4-phenyl-piperazinium Iodide −1.057 1.4522E−01 no Cholinergic Agonist −2.2053 Cyclothiazide −0.907 1.8221E−01 no Glutamate Agonist AMPA −2.7150 8-Cyclopentyl-1-3-dipropylxanthine −0.070 4.7201E−01 no Adenosine Antagonist A1 −21.9125 8-Cyclopentyl-1-3-dimethylxanthine −0.125 4.5035E−01 no Adenosine Antagonist A1 −20.3794 (±)-CPP 0.321 3.7398E−01 no Glutamate Antagonist NMDA −4.3608 2-Cyclooctyl-2-hydromethylamine hydrochloride −0.575 2.8276E−01 no Neurotransmission Inhibitor PNMT −3.8688 5-Carboxamidotryptamine maleate 1.667 4.7711E−02 no Serotonin Agonist 5-HT7 −19.4950 7-Chlorokynurenic acid 1.241 1.0733E−01 no Glutamate Antagonist NMDA −4.9223 (±)-CGP-12177A hydrochloride −1.611 5.3544E−02 no Adrenoceptor Agonist beta −15.3977 S-(−)-Carbido

−2.314 1.0$324−02 no Biochemistry Inhibitor Aromatic amino acid decar −8.9751 (±)-Chloro-APB dihydrochloride −0.111 4.5591E−01 no Dopamine Agonist D1 −6.3740 Y-27632 dihydrochloride −0.125 4.5307E−01 no Phosphorylation Inhibitor ROCK −7.9142 2-Chloroadenosine triphosphate tetrasodium 1.149 1.2531E−01 no P2 Receptor Agonist P2Y −8.8552 (+)-Cyclazocine 0.812 2.7040E−01 no Opioid Antagonist −1.0738 Capsazepine 1.260 1.0388E−01 no Vaniloid Agonist −7.7040 Chlormezanone −0.947 1.7194E−01 no Neurotransmission Modulator Muscle relaxant −8.2721 8-(3-Chlorostyryl)caffeine −1.214 1.1231E−01 no Adenosine Antagonist A2A −12.4931 CGS-15943 0.178 4.2922E−01 no Adenosine Antagonist A1 −6.2372 Cirazoline hydrochloride 0.424 3.3580E−01 no Adrenoceptor Agonist alpha1A −6.5318 CGP 20712A

0.849 2.5815E−01 no Adrenoceptor Antagonist beta1 −13.7874 (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine 1.233 1.0878E−01 no Glutamate Agonist mGluR2 −5.8299 CNOX disodium −1.904 2.8471E−02 no Glutamate Antagonist AMPA/Kainate −8.1220 CX 546 −1.050 1.4686E−01 no Glutamate Modulator AMPA −5.5185 Chloro-IB-MECA −0.847 1.9846E−01 no Adenosine Agonist A3 −5.2593 WB-4101 hydrochloride −2.247 1.2321E−02 no Adrenoceptor Antagonist alpha1A −7.3187 DNOX 0.931 1.7599E−01 no Glutamate Antagonist Kainate/quisqualate −6.4394 DBO-83 −1.279 1.0038E−01 no Cholinergic Agonist Nicotinic −7.5674 Dephostatin 0.621 2.8732E−01 no Phosphorylation Inhibitor CD45 Tyrosine Kinase −3.9458 3-deazaadenosine 1.770 3.8388E−02 no Immune System Inhibitor −6.0324 (Z)-Gugglesterone 3.205 6.7567E−04 no Lipid Signaling Antagonist FRX −10.5383 Danazol 2.152 1.5713E−02 no Hormone Inhibitor −15.4776 N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide 1.918 2.7694E−02 no Benzodiazepine Ligand Mitochondria −7.3781 SP500125 −1.038 2.3536E−02 no Phosphorylation Inhibitor c-JNK −8.4226 Diazoxide 0.045 4.8201E−01 no K+ Channel Activator ATP-sensitive −3.3923 3,4-Dihydroxyphenylacetic acid −0.583 2.7988E−01 no Dopamine Metabolite −10.2325 Dantrolene sodium 0.798 2.1230E−01 no Intracellular Calcium Inhibitor Release −8.4822 DCEBIO 0.810 2.0900E−01 no K+ Channel Activator hlK1 −3.8055 1-Deoxynojirimycin hydrochloride 1.242 1.0713E−01 no Biochemistry Inhibitor alpha-glucosidase −6.5289 L-3,4-Dihydroxyphenylalanine 2.440 7.3488E−03 no Dopamine Precursor −9.9117 Dipyridamole −0.727 2.3372E−01 no Adenosine Inhibitor −1.9619 Doxazosin mesylate −1.361 3.1346E−02 no Adrenoceptor Blocker alpha1 −2.6413 Doxycycline hydrochloride −0.558 2.8340E−01 no Antibiotic Protein synthesis −14.0343 6,7-ADTN hydrobromide 0.357 3.8058E−01 no Dopamine Agonist −6.3543 Dipropyldopamine hydrobromide −1.348 8.9197E−02 no Dopamine Agonist −3.0223 Amfonelic acid 0.468 3.1277E−01 no Dopamine Modulator −13.3958 Icilin 1.643 5.0157E−02 no Neurotransmission Agonist CMR1 −6.3622 (±)-SKF-38393 hydrochloride 1.280 1.0030E−01 no Dopamine Antagonist D1 −8.8933 R(+)-SCH-23390 hydrochloride 1.375 8.4525E−02 no Dopamine Antagonist D1 −2.8442 (±)-DOI hydrochloride −1.345 8.9370E−02 no Serotonin Agonist 5-HT2/5-HT1C −1.8081 (±)-2,3-Dichloro-alpha-methylbenzylamine hydrochloride −2.251 1.2197E−02 no Neurotransmission Inhibitor PNMT −3.2749 4-DAMP methioxide 0.331 3.7027E−01 no Cholinergic Antagonist M3 −4.8290 1,2-Dipropyl-7-methylxanthine −0.089 4.5458E−01 no Adenosine Antagonist A2 −17.0207 Propofol 0.377 3.5315E−01 no Cholinergic Inhibitor Muscarinic −2.8649 Dextrorphan D-tartrate 1.569 5.8358E−02 no Glutamate Antagonist NMDA −3.2343 R(±)-Butylindazone 0.029 4.8834E−01 no Ion Pump Inhibitor K+/Cl− transport −9.4107 DPMA 0.038 4.8553E−01 no Adenosine Agonist A2 −4.6683 3,5-Dinitrocatechol −0.529 2.9828E−01 no Neurotransmission Inhibitor COMT −6.6346 N,N-Dipropyl-5-carboxamidotryptamine maleate −1.730 4.1815E−02 no Serotonin Agonist 5-HT1A −13.3021 6,7-Dichloroquinoxaline-2,3-dione 0.127 4.4932E−01 no Glutamate Antagonist NMDA-glycine −3.3370 3,7-Dimethyl-1-propargylxanthine 1.454 7.3015E−02 no Adenosine Antagonist A2 −15.2349 5,7-Dichlorolynurenic acid 0.281 1.8378E−01 no Glutamate Antagonist NMDA-glycine −4.6883 4-Diphenylacetoxy-N-(2-chloroethyl)piperidine hydrochloride 0.864 1.9386E−01 no Cholinergic Antagonist Muscarinic −1.3381 1,10-Diaminodecane 0.139 4.4460E−01 no Glutamate Agonist (inv NMDA-polyamine −2.0129 Dihydro-beta-erythroidine hydrobromide −1.788 3.6854E−02 no Cholinergic Antagonist nAch −2.8674 N-(3,3-Diphenylpropyl)glycinamide −1.243 1.0891E−01 no Glutamate Blocker NMDA −5.7248 Glibenclamide −0.360 3.5941E−01 no K+ Channel Blocker ATP-dependent −8.7301 GW2974 −0.516 3.0279E−01 no Phosphorylation Inhibitor EGFR/ErbB-2 −12.2358 Guranfacine hydrochloride 0.927 1.7695E−01 no Adrenoceptor Agonist alpha2 −2.0297 L-Glutamic acid hydrochloride −0.473 3.1822E−01 no Glutamate Agonist −2.3031 DBO-83 −1.279 1.0038E−01 no Cholinergic Agonist Nicofinic −7.5874 Dephostalin 0.621 2.6732E−01 no Phosphorylation Inhibitor CD45 Tyrosine Kinase −3.9458 3-deazaadenosine 1.770 3.8360E−02 no Immune System Inhibitor −6.0324 (Z)-Gugglesterone 3.205 6.7567E−04 no Lipid Signaling Antagonist FRX −10.5383 Danazol 2.152 1.5713E−02 no Hormone Inhibitor −15.4776 N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide 1.910 2.7694E−02 no Benzodiazepine Ligand Mitochondria −7.3781 SP600125 −1.965 2.3538E−02 no Phosphorylation Inhibitor c-JNK −8.4226 Diazoxide 0.045 4.8201E−01 no K+ Channel Activator ATP-sensitive −3.3923 3,4-Dihydroxyphenylacetic acid −0.383 2.708E−01 no Dopamine Metabolite −10.2325 Dantrolene sodium 0.798 2.1230E−01 no Intracellular Calcium Inhibitor Release −8.4822 DCEBIO 0.379 2.0900E−01 no K+ Channel Activator hlK1 −3.8055 1-Deoxynojirimycin hydrochloride 1.242 1.0713E−01 no Biochemistry Inhibitor alpha-glucosidase −0.5368 L-3,4-Dihydroxyphenylalanine 2.440 7.3488E−03 no Dopamine Precursor −0.9117 Dipyridamole −0.727 2.3372E−01 no Adenosine Inhibitor −1.9618 Doxacosin mesylate −1.861 3.1346E−02 no Adrenoceptor Blocker alpha1 −2.6413 Doxycycline hydrochloride −0.558 2.8849E−01 no Antibiotic Protein synthesis −14.0343 6,7-ADTN hydrobromide 0.357 3.6058E−01 no Dopamine Agonist −6.3543 Dipropyldopamine hydrochloride −1.346 8.9197E−02 no Dopamine Agonist −3.0223 Amfonelic acid 0.488 3.1277E−01 no Dopamine Modulator −13.3956 Icilin 1.643 5.0157E−02 no Neurotransmission Agonist CMR1 −6.3622 (±)-SKF-38393 hydrochloride 1.260 1.0030E−01 no Dopamine Antagonist D1 −8.8933 R(+)-SCH-23390 hydrochloride 1.375 8.4625E−02 no Dopamine Antagonist D1 −2.8442 (±)-DOI hydrochloride −1.345 8.9370E−02 no Serotonin Agonist 5-HT2/5-HT1C −1.8081 (±)-2,3-Dichloro-alpha-methylbenzylamine hydrochloride −2.251 1.2197E−02 no Neurotransmission Inhibitor PNMT −3.2749 4-DAMP methiodide 0.331 3.7027E−01 no Cholinergic Antagonist M3 −4.8290 1,3-Dipropyl-7-methylxanthine −0.089 4.6458E−01 no Adenosine Antagonist A2 −17.0207 Propofol 0.377 3.5315E−01 no Cholinergic Inhibitor Muscarinic −2.8649 Dextrorphan-7-tartrate 1.569 5.8358E−02 no Glutamate Antagonist NMDA −3.2343 R(±)-Butylindazone 0.029 4.8834E−01 no Ion Pump Inhibitor K+/Cl− transport −9.4197 DPMA 0.035 4.8553E−01 no Adenosine Agonist A2 −4.8683 3,4-Dinitrocatechol −0.529 2.9828E−01 no Neurotransmission Inhibitor COMT −6.6346 N,N-Dipropyl-5-carboxamidoxytryptamine maleate −1.730 4.1815E−02 no Serotonin Agonist 5-HT1A −13.3021 6,7-Dichloroquinoxaline-2,3-dione 0.127 4.4932E−01 no Glutamate Antagonist MMDA-glycine −3.3370 3,7-Dimethyl-1-propargylxanthine 1.454 7.3015E−02 no Adenosine Antagonist A2 −15.2349 5,7-Dichlorolynurenic acid 0.901 1.8378E−01 no Glutamate Antagonist NMDA-glycine −4.6989 4-Diphenylacetoxy-N-(2-chloroethyl)piperidine hydrochloride 0.864 1.9365E−01 no Cholinergic Antagonist Muscarinic −1.3361 1,10-Diaminodecane 0.139 4.4460E−01 no Glutamate Agonist (inv NMDA-polyamine −2.0129 Dihydro-beta-erythroidine hydrobromide −1.788 3.6854E−02 no Cholinergic Antagonist nAch −2.8674 N-(3,3-Diphenylpropyl)glycinamide −1.243 1.0691E−01 no Glutamate Blocker NMDA −5.7246 Glibenclamide −0.860 3.5941E−01 no K+ Channel Blocker ATP-dependent −8.7301 GW2974 −0.516 3.0279E−01 no Phosphorylation Inhibitor EGFR/ErbB-2 −12.2358 Guanfacine hydrochloride 0.927 1.7695E−01 no Adrenoceptor Agonist alpha2 −2.0297 L-Glutamic acid hydrochloride −0.473 3.1822E−01 no Glutamate Agonist −2.3031 L-Glutamine 0.828 2.0389E−01 no Glutamate Agonist −6.0432

-

indole di-trifluoroacetate −0.204 4.1929E−01 no Opioid Antagonist kappa −9.3192 GW1929 0.015 4.9398E−01 no Transcription Agonist PPAR-gamma −9.5700 GW2074 −0.162 4.3570E−01 no Phosphorylation Inhibitor Raf1 kinase −8.2139 GW7647 −0.992 1.6052E−01 no Transcription Agonist PPAR-alpha −12.1570 Galfamine trichloride −0.916 1.7995E−01 no Cholinergic Antagonist M2 −4.7485 S-Ethylisoithiourea hydrobromide −1.599 5.4874E−02 no Nitric Oxide Inhibitor NOS −4.2580 Edrophonium chloride −0.806 2.1001E−01 no Cholinergic Inhibitor Acetylcholinesterase −5.3039 Ebselen −0.251 4.0072E−01 no Leukotriene Inhibitor −2.2253 rac-2-Ethoxy-3-hexadecanamido-1-propylphosphocholine −1.269 1.0223E−01 no Phosphorylation Inhibitor PKC −13.3506 rac-2-Ethoxy-3-octadecanamido-1-propylphosphocholine −1.112 1.3298E−01 no Phosphorylation Inhibitor PKC −12.3289 N-Ethyimaleimide −0.028 4.8877E−01 no Biochemistry Inhibitor Isocitrate dehydrogenase −3.3843 (−)-Epinephrine bitartrate −0.530 2.9791E−01 no Adrenoceptor Agonist −13.0202 (±)-Epinephrine hydrochloride −0.329 3.7149E−01 no Adrenoceptor Agonist −12.7284 E

imide −0.612 2.7014E−01 no Anticonvulsant −1.4347 En

−1.143 1.2644E−01 no Phosphorylation Inhibitor PP2A −4.0878 Emodin −0.463 3.1438E−01 no Phosphorylation Inhibitor p56lck TK −5.2573 (−)-Physosfigmine −0.218 4.1377E−01 no Cholinergic Inhibitor Cholinesterase −3.2224 NBI 27914 0.134 4.4651E−01 no Neurotransmission Antagonist CRF1 −3.9632 beta-Estradiol −0.582 2.8358E−01 no Hormone Estrogen −12.0545 Estrone 0.041 4.8372E−01 no Hormone Estrogen −13.0120 Methyl beta-carboline-3-carboxylate 0.060 4.7598E−01 no Benzodiazepine Agonist −9.2192 N-Methyl-beta-carboline-3-carboxamide 0.699 2.4235E−01 no GABA Antagonist GABA-A −9.5740 Methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate −1.326 9.2463E−02 no Benzodiazepine Agonist −5.1499 (−)-Eseroline fumarate 0.634 2.6308E−01 no Cholinergic Inhibitor Cholinesterase −5.6206 (S)-ENBA 0.209 4.1767E−01 no Adenosine Agonist A1 −8.4799 erythro-9-(2-Hydroxy-3-nonyl)adenine hydrochloride −0.756 2.2197E−01 no Adenosine Inhibitor Adenosine deaminase −1.3832 Ergocristine 0.409 3.4172E−01 no Dopamine Agonist −27.2858 Felbamate −0.459 3.2327E−01 no Glutamate Antagonist −8.5534 Fusidic acid sodium 2.045 2.0427E−02 no Cell Cycle Inhibitor −9.8579 Fenoterol hydrobromide −1.841 3.2821E−02 no Adrenoceptor Agonist beta2 −10.3422 S-(+)-Fluoxetine hydrochloride −0.809 2.0932E−01 no Serotonin Inhibitor Reuptake −9.1211 R-(−)-Fluoxetine hydrochloride −0.129 4.4906E−01 no Serotonin Inhibitor Reuptake −9.1211 Fluvoxamine maleate 0.132 4.4737E−01 no Serotonin Inhibitor Reuptake −9.4524 1-(4-Fluorobenzyl)-5-methoxy-2-methylindole-3-acetic acid −0.538 2.9543E−01 no Multi-Drug Resistance Inhibitor MRP1 −9.0898 Funegretate sodium 0.364 3.5800E−01 no Phosphorylation Inhibitor Thromboxane synthase −12.3958 Fiduxosin hydrochloride 0.200 4.2056E−01 no Adrenoceptor Antagonist alpha1 −5.1858 Furosamide 1.889 2.9456E−02 no Ion Pump Inhibitor Na+,K+,Cl− cotransport −5.9592 p-Fluoro-L-phenylalamine −0.702 2.4126E−01 no Neurotransmission Substrate Tyrosine Hydroxylase −4.5617 Fenofibrate −2.116 1.7190E−02 no Transcription Agonist PPAR-alpha −0.2642 Fenspiride hydrochloride −0.578 2.8223E−01 no Adrenoceptor Antagonist alpha −0.7723 Flumazenil −0.386 3.6702E−01 no Benzodiazepine Antagonist −10.4543 Foliosidine −0.097 4.6140E−01 no Anticonvulsant −5.0395 Fusaric acid −0.141 4.4382E−01 no Dopamine Inhibitor Dopamine beta-hydroxylase −7.0076 Flecaimide acelate −1.498 8.7005E−02 no Na+ Channel Blocker −5.4913 Fenoldopam bromide 0.052 4.7919E−01 no Dopamine Agonist D1 −7.5224 Forskolin −1.331 9.1668E−02 no Cyclo Nucleotides Activator Adenylate cyclase −4.1972 Famotidine 0.065 4.7811E−01 no Histamide Antagonist H2 −7.5810 FSCPX 0.782 2.1697E−01 no Acenosine Antagonist A1 −25.0121 Farne

 acid 0.908 1.8244E−01 no G protein Antagonist Ras −4.1651 Flunarizine dihydrochloride 0.395 3.4627E−01 no Ion Pump Blocker Na+/Ca2+ channel −1.9671 5-fluoro-5′-deoxyuridine 0.379 3.5246E−01 no DNA Metabolism Inhibitor −2.9280 Flupirtine aceleate −0.484 3.1420E−01 no Glutamate Antagonist NMDA −9.8407 Flutamide −0.113 4.5490E−01 no Hormone Inhibitor Androgen −7.3424 Fexofenamine hydrochloride −0.757 2.2445E−01 no Histamide Antagonist HRH1 −5.6445 Formoterol −0.838 2.0104E−01 no Adrenoceptor Agonist beta2 −16.0812 Felodipine −0.968 1.6707E−01 no Ca2+ Channel Blocker L-type −10.2014 Fluspirilene 1.589 5.6001E−02 no Dopamine Antagonist D2/D1 −5.8124 Furafylline 1.025 1.5277E−01 no Biochemistry Inhibitor P450IA2 −16.0242 FPL 64176 −1.099 1.3591E−01 no Ca2+ Channel Activator L-type −6.8541 Fluoxeiine hydrochloride −1.311 9.4858E−02 no Serotonin Inhibitor Reuptake −9.1211 GR 125487 sulfamate salt −0.194 4.2300E−01 no Serotonin Antagonist 5-HT4 −4.2855 IEM-1460 0.685 2.4674E−01 no Glutamate Inhibitor AMPA −5.2580 Ibudilast 0.379 3.5244E−01 no Cyclic Nucleotides Inhibitor PDE IV −6.2032 Imidazole-1-acetic acid hydrochloride −0.922 1.7200E−01 no GABA Antagonist GABA-C −12.6089 Indirubin-3′-oxime −0.397 3.4587E−01 no Phsophorylation Inhibitor CDK −8.4387 Imazodan 0.462 3.2217E−01 no Cyclic Nucleotides Inhibitor PDE II −12.4077 Ipratropium bromide −0.308 3.7904E−01 no Cholinergic Antagonist Muscarinic −8.9698 2-Iodomelatonin −0.135 4.4637E−01 no Melatonin Agonist −7.1283 SB 228357 0.034 4.8634E−01 no Serotonin Antagonist 5-HT2B/2C −4.5878 IMID-4F hydrochloride −1.906 2.8337E−02 no K+ Channel Blocker −3.6024 R(−)-Ioproterenol (+)-bitartrate −1.465 6.8743E−02 no Adrenoceptor Agonist beta −13.6004 Isog

roine hydrochloride −2.220 1.3208E−02 no GABA Agonist GABA-A, GABA-C −5.7435 Guxacine hydrochloride −1.345 8.9234E−02 no GABA Inhibitor Uptake −5.2169 (±)-AMPA hydrobromide −0.427 3.3461E−01 no Glutamate Agonist AMPA/kainate −9.1686 Muscinet hydrobromide 0.186 4.2612E−01 no GABA Agonist GABA-A, GABA-C −6.3913 Guanabens acetate −1.906 2.9344E−02 no Adrenoceptor Agonist alpha2 −5.3611 gamma-D-Glutamylaminomethylsulfonic acid −0.046 4.8146E−01 no Glumatate Antagonist Kainate −6.9425 Gipzide −0.830 2.0341E−01 no K+ Channel Blocker ATP-sensitive −13.3300 GYK1 52895 −1.258 1.0419E−01 no Dopamine Inhibitor Reuptake −0.3735 Gabapentin 0.864 1.8641E−01 no Anticonvulsant −4.8782 (±)-Vanillylmandelic acid −1.811 3.5052E−02 no Adrenoceptor Metabolite −1.2797 6-Hydroxymelatonin 0.377 3.5318E−01 no Metatonin Metabolite −15.2014 4-Hydroxy-3-methoxyphenylacetic acid −0.567 2.8528E−01 no Dopamine Metabolite −2.3077 MHPG piperazine 0.053 4.7896E−01 no Adrenoceptor Metabolite −2.0185 Hypotaurine 0.275 3.9158E−01 no Cell Stress Inhibitor Antioxidant −3.4031 LFM-A13 4.500 34002E−08 no Phosphorylation Inhibitor BTK −7.8485 Luteolin −1.323 9.2973E−02 no Cell Stress Inhibitor Antioxidant −12.5139 L-855.240 −0.121 4.5183E−01 no Thromboxanene Antagonist TXA2 −9.983 Loratadine −1.823 3.41

2 no Histamine Antagonist HRH

−7.9079 (−)-Teramisole hydrochloride −1.866 3.1005E−02 no Phosphorylation Inhibitor −9.8745 L-855,708 −0.613 2.6988E−01 no Benzodiezepine Ligand GABA-A −11.3947 LY-294,002 hydrochloride −1.217 1.1184E−01 no Phosphorylation Inhibitor FI3K −3.1040 Loxapine succinate −0.748 2.2732E−01 no Dopamine Antagonist −4.0117 (±)-Ibotenic acid −1.550 4.9495E−02 no Glutamate Agonist NMDA −7.9415 Isoth

ine mesylate −0.639 2.6138E−01 no Adrenoceptor Agonist beta −8.8817 (±)-Ibuprofen −0.262 3.9553E−01 no Prostaglandin Inhibitor COX −8.3439 IIK7 −0.354 3.6152E−01 no Melatonin Agonist −8.8271 (±)-Isopoterenol hydrochloride −0.572 2.8378E−01 no Adrenoceptor Agonist beta −14.1845 3-Isobutyl-1-methylxanthine −0.774 2.1947E−01 no Adenosine Inhibitor Phosphodiesterase −16.0203 Idazoxan hydrochloride −1.448 7.3866E−02 no Imidozoline Ligand I1/12 −6.8373 1(5-Is

nolinylsulfonyl)-3-me

 

de 0.477 3.1672E−01 no Phosphorylation Inhibitor PKC −2.8972 (−)-Isoproterenol hydrochloride 0.237 4.0648E−01 no Adrenoceptor Agonist beta −14.1845 1-(5-Isoquinolinysulfonyl)-2-methylpiperazine dihydrochloride 0.335 3.6874E−01 no Phosphorylation Inhibitor PKA/PKC −3.0203 Imipramine hydrochloride −0.527 2.9903E−01 no Serotonia Blocker Reuptake −1.0708 Isoxarthoptenin 0.234 4.0752E−01 no Cell Stress Metabolite −7.9514 Iproniazid phosphate −0.249 4.0158E−01 no Neurotransmission Inhibitor MAD −8.4760 S(+)-Isoproterenol(+)-bitartrate −0.295 3.8350E−01 no Adrenoceptor beta −13.6004 L-N6-(1-Iminoethyl)lysine hydrochloride −0.381 3

no Nitric oxide Inhibitor BIOS −6.5483 3-Iodo-L-tyrosine −0.048 4.806

no Neurotransmission Inhibitor Tyrosine hydroxylase −3.7497 L-N5-(1-Iminoethyl)omi

 hydrochloride −0.934 1.7519E−01 no Nitric Oxide Inhibitor NOS −6.6284 Ivermeotin 1.507 8.5655E−02 no Cholinergic Modulator alpha7 nACh −2.3255 Imiloxan hydrochloride −0.988 1.6160E−01 no Adrenoceptor Antagonist alpha2B −5.9673 CR2945 0.545 2.9285E−01 no Choleoystokinin Antagonist CCK-B −13.6579 S(+)-Ibuprofen −0.733 2.3164E−01 no Prostaglandin Inhibitor COX −8.3439 p-

 hydrochloride −0.161 4.3619E−01 no Adrenoceptor Agonist alpha2 −7.1078 R(+)-IAA-

−0.010 4.9595E−01 no Cl-Channel Inhibitor −8.5026 Indatraline hydrochloride −0.724 2.3455E−01 no Dopamine Inhibitor Reuptake −0.1381 loietamine hydrochloride −0.759 2.2398E−01 no Neurotransmission Analog −4.5840 ICI 204,448 hydrochloride −0.304 3.5809E−01 no Opioid Agonist kappa −2.3593 ICI 118,551 hydrochloride 1.101 1.3555E−01 no Adrenoceptor Antagonist beta2 −65568 Imetit dihydrobromide −0.245 4.0313E−01 no Histamine Agonist H3 −13.0801 1,5-Isoquinolinediol 0.027 4.8934E−01 no Apoptosis Inhibitor PARS −5.7715 IS-MECA −1.089 1.3588E−01 no Adenosine Agonist A3 −3.8357 3-(1H-Imidazol-4-yl)propyl di(p-fuuorophenyl)methyl ether −0.015 4.9415E−01 no Histamine Antagonist H3 −5

Isonipso

 acid −0.457 3.2387E−01 no GABA Agonist GABA-A −4.4

JWH-015 0.822 2.6688E−01 no Cannabinoid Agonist CB2 −4.4913 JL-18 −0.288 3.8739E−01 no Dopamine Antagonist D4 > D2 −8.

Kainic acid −0.317 3.7567E−01 no Glutamate Agonist Kainate −5.

03 LFM-A13 4.500 3.4002E−08 no Phosphorylation Inhibitor BTK −7.6465 Luteolin −1.323 9.2973E−02 no Cell Stress Inhibitor Antioxidant −12.5139 L-555,240 −0.121 4.5183E−01 no Thromboxane Antagonist TXA2 −

3 Loratadine −1.823 3.4160E−02 no Histamine Antagonist HRH1 −7.9079 (−)-Tetramisole hydrochloride −1.868 3.1005E−02 no Phosphorylation Inhibitor −9.6745 L-855,708 −0.513 2.6988E−01 no Benzodiazepine Ligand GABA-A −11.3947 LY-294,002 hydrochloride −1.217 1.1184E−01 no Phosphorylation Inhibitor PI2K −3.1040 Loxapine succinate −0.748 2.2732E−01 no D

Antagonist −4.0117 (±)-Ibotenic acid −1.850 4.9495E−02 no Glutamate Agonist NMDA −7.9415 Isotharine mesylate −0.839 2.6138E−01 no Adrenoceptor Agonist beta −8.8817 (±)-Ibuprofen −0.262 3.9553E−01 no Prostaglandin Inhibitor COX −8.3439 IIK7 −0.354 3.6152E−01 no Melatonin Agonist −8.6271 (±)-Isopoterenol hydrochloride −0.572 2.8378E−01 no Adrenoceptor Agonist beta −14.1845 3-Isobutyl-methyl

e −0.774 2.1947E−01 no Adenosine Inhibitor Phophodiesterase −16.0203 Idazoxan hydrochloride −1.448 7.

E−32 no Imidazoline Ligand I1/I2 −6.8373 1(5-Isoquinolinylsulfonyl)-2-methylpiperazine dihyedichloride 0.477 3.1672E−01 no Phosphorylation Inhibitor PKO −2.8972 (−)-Isoproterenol hydrochloride 0.237 4.0648E−01 no Adrenoceptor Agonist beta −14.1845 1-(5-Isoquinolinysulfonyl)-2-methylpiperazine dihydrochloride 0.335 3.6874E−01 no Phosphorylation Inhibitor PKA/PKC −3.0203 Imipramine hydrochloride −0.527 2.9903E−01 no Serotonia Blocker Reuptake −1.0708 Isoxanthoptenin 0.234 4.0752E−01 no Cell Stress Metabolite −7.9514 Iproniazid phosphate −0.249 4.0158E−01 no Neurotransmission Inhibitor MAO −8.4760 S(+)-Isoproterenol(+)-bitartrate −0.296 3.8350E−01 no Adrenoceptor beta −13.6004 L-N

-(1-lmir

 hydrochloride −0.381 3.5164E−01 no Nitric Oxide Inhibitor INOS −6.5483 3-Iodo-L-tyrosine −0.048 4.8088E−01 no Neurotransmission Inhibitor Tyrosine hydroxylase −3.7497 L-N5-(1mir

 hydrochloride −0.934 1.7519E−01 no Nitric Oxide Inhibitor NOS −6.6284 Ivermectin 1.507 8.5655E−02 no Cholinergic Modulator alpha7 nACh −2.3255 Imiloxan hydrochloride −0.988 1.6160E−01 no Adranoceptor Antagonist alpha2B −5.9673 CR 2945 0.545 2.9285E−01 no Choleoystokinin Antagonist CCK-B −13.6579 S(+)-Ibuprofen −0.733 2.3164E−01 no Prostaglandin Inhibitor COX −8.3439 p-

 hydrochloride −0.101 4.3619E−01 no Adrenoceptor Agonist alpha2 −7.1078 R(+)-IAA-94 −0.010 4.9595E−01 no Cl-Channel Inhibitor −8.5026 Indatraline hydrochloride −0.724 2.3465E−01 no Dopamine Inhibitor Reuptake −0.1381 Ioietamine hydrochloride −0.759 2.2398E−01 no Neurotransmission Analog −4.5840 ICI 204,449 hydrochloride −0.364 3.5809E−01 no Opioid Agonist kappa −2.3593 ICI 118,551 hydrochloride 1.101 1.3555E−01 no Adrenoceptor Antagonist beta2 −65568 Imetit dihydrobromide −0.245 4.0313E−01 no Histamine Agonist H3 −13.0801 1,5-Isoqui

0.027 4.8934E−01 no Apoptosis Inhibitor PARS −5.7715 IS-MECA −1.089 1.3588E−01 no Adenosine Agonist A3 −3.8357 3-(1H-Imidazol-4-yl)propyl di(p-fluorophenyl)methyl ether −0.015 4.9415E−01 no Histamine Antagonist H3 −5.8768 Isonipso

 acid −0.457 3.2387E−01 no GABA Agonist GABA-A −4.8582 JWH-015 0.822 2.8688E−01 no Cannabinoid Agonist CB2 −4.4913 JL-1B −0.285 3.8739E−01 no Dopamine Antagonist D4 > D2 −8.5500 Kainic acid −0.317 3.7567E−01 no Glutamate Agonist Kainate −5.9803 Keio

0.556 2.7892E−01 no Multi-Drug Resistance Inhibitor Cytochrome P450c17 −0.0583 Keforolac tris salt −0.726 2.3405E−01 no Prostaglandin Inhibitor COX −8.3587 Ketoprofen −1.164 1.2226E−01 no Prostaglandin Inhibitor COX-1 −9.3283 K 185 0.587 2.8521E−01 no Melatonin Antagonist −5.3276 Keto

 fumerate 0.957 1.6921E−01 no Histamine Antagonist HRH1 −10.4823 Kynurenic acid 0.702 2.4140E−01 no Glutamate Antagonist NMDA-Glycine −6.8297 Kerpaullone −1.555 5.9978E−02 no Phosphorilation Inhibitor CDK1, CDK2, CDK5 −10.0974 Karakoline −1.625 5.2047E−02 no Cholinergic Antagonist Nicotinic −3.9500 L-701.324 0.451 3.2590E−01 no Glutamate Antagonist NMDA-Glycine −2.

37 loxoprofen −0.883 1.8853E−01 no Prostaglandin Inhibitor COX −10

Labetalol hydrochloride −1.097 1.3628E−01 no Adrenoceptor Antagonist beta −7.9305 L-162,313 0.792 2.1410E−01 no Neurotransmission Agonist AT1 −14.2550 Lidocaine N-methyl hydrochloride −0.583 2.4738E−01 no Na+ Channel Blocker −7.4131 LY-367,265 −0.407 3.4202E−01 no Serotonin Antagonist Reptake −10.9577 L-388,899 0.201 3.8555E−01 no Neurotransmission Antagonist Oxytocin receptor −7.

77 Lomefloxacin hydrochloride 0.137 4.4536E−01 no Antibiotic Inhibitor DNA Gyrase −12.1001 Lamotrigine −1.095 1.3681E−01 no Anticonvulsant −2.3009 alpha-Lobeline hydrochloride 0.550 2.9121E−01 no Cholinergic Agonist Nicotine −2.4879 Loperamide hydrochloride −0.498 3.0938E−01 no Opioid Ligand −4.0032 Lonidamine 0.436 3.3148E−01 no Cell Stress Inhibitor Mitochondrial hexokinase −5.7024

indicates data missing or illegible when filed

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1. A method for identifying putative modulators of proliferation, differentiation, renewal, or a combination thereof of neural precursor cells, neural progenitor cells and self-renewing and multipotent neural stem cells (NSCs), said method comprising incubating a neurosphere culture in the presence of a test agent and determining the effect of the test agent on proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells, NSCs, or a combination thereof wherein a difference in proliferation, differentiation and/or renewal of neural precursor cells, neural progenitor cells, NSCs, or a combination thereof in the culture compared with a control neurosphere culture indicates that the test agent is a putative modulator.
 2. A method according to claim 1, further comprising assessing the selectivity, potency, or a combination thereof of a putative modulator by comparing a neurosphere selectivity ratio of the modulator in a normal astrocyte cell line to that of a control.
 3. A method according to claim 2, wherein the control comprises an astrocyte cell line treated with cycloheximide, etoposide or carboplatin and the neurosphere selectivity ratio is greater than
 3. 4. A composition comprising one or more putative modulator using a method of claim 1 in a therapeutically effective amount for inhibiting proliferation, differentiation, renewal, or a combination thereof of diseased neural precursor cells, neural progenitor cells, NSCs, or a combination thereof and a pharmaceutically acceptable carrier, excipient or diluent.
 5. A composition according to claim 4, wherein the therapeutically effective amount is effective for treatment of a brain or CNS cancer.
 6. A composition according to claim 5, wherein the brain or CNS cancer is a primary CNS tumor.
 7. A composition according to claim 4, wherein the therapeutically effective amount is effective for treatment of a brain tumor having a genetic profile resembling that of normal and embryonic neural precursor cells.
 8. A composition according to claim 4, wherein the therapeutically effective amount is effective for treatment of a brain tumor enriched for cancer stem cells.
 9. A composition according to claim 8, wherein the one or more modulator is selected from the group consisting of a dopamine receptor antagonist, a dopamine receptor agonist, an acetylcholine receptor antagonist, an NMDA receptor antagonist, an opioid receptor agonist, a retinoic acid receptor agonist, a JAK3 antagonist, a p38 MAPK antagonist, a serotonin receptor agonist, and a vanilloid receptor agonist.
 10. A composition comprising a compound selected from the group consisting of a dopamine receptor antagonist, a dopamine receptor agonist, an acetylcholine receptor antagonist, an NMDA receptor antagonist, an opioid receptor agonist, a retinoic acid receptor agonist, a JAK3 antagonist, a p38 MAPK antagonist, a serotonin receptor agonist, and a vanilloid receptor agonist in a dosage effective for inducing proliferation of neural stem cells into an increased amount of neural progenitor cells, or for inducing proliferation of neural stem cells or neural progenitor cells into an increased amount of neural cells.
 11. A composition according to claim 10, comprising a compound selected from the group consisting of (±)butaclamol, R(−) propylnorapomorphine, apomorphine, cis-(Z) flupenthixol, ifenprodil, hexahydro-sila-difenidol, ifenprodil tartrate, carbetapentane citrate, fenretinide, WHI-P131, SB 202190, p-aminophenethyl-m-trifluoromethylphenyl piperazine (PAPP), and dihydrocapsaicin in a therapeutically effective amount for treatment of a brain or CNS cancer.
 12. A method for treating a condition requiring modulation of proliferation, differentiation, renewal, or a combination thereof of diseased neural precursor cells, early neural progenitor cells, NSCs or a combination thereof, said method comprising administering to a subject in need thereof a therapeutically effective amount of a composition according to claim
 11. 13. A method according to claim 12, wherein the condition is a brain or CNS cancer.
 14. A method according to claim 12, wherein the condition is a primary CNS tumor.
 15. A method for treating a condition requiring modulation of proliferation, differentiation renewal, or a combination thereof of normal neural precursor cells, early neural progenitor cells, NSCs, or a combination thereof, said method comprising administering to a subject in need thereof a therapeutically effective amount of a composition according to claim
 11. 16. A method according to claim 15, wherein the condition is a neurological disorder or neurological damage.
 17. A method according to claim 16, wherein the condition is Down Syndrome, Parkinson disease, Huntington's Chorea, pathogenic psychotic conditions, schizophrenia, cognitive dysfunction and dementia, or a central nervous system trauma. 